Graduate School Neurosciences Amsterdam & Rudolf ... - ONWA

CONTENTSDear PhD-student 3Route description to Conference Center Woudschoten 4(see also www.woudschoten.nl)General information 5Program of the meeting 6Blitz session 8Poster sessions 10Instructions for making a poster 13Tips for an oral presentation 14Abstracts 15Abstract Swammerdam Lectures (Bert Sakmann) 17Abstracts oral presentations 18Abstracts posters 43Lists of participants (incl. e-mail-addresses, telephone-numbers) 93Lay out cover: C. Oomen and Els MøstPicture cover: Roy Raymann, Kristallwelt, Innsbruck, Austria2

Dear PhD student,Welcome to the 13 th Annual Meeting of PhD-students of the Graduate School Neurosciences Amsterdamand the Rudolf Magnus Graduate School of Neuroscience Utrecht at Conference Center Woudschoten inZeist.This meeting is organized for and by PhD-students and offers the opportunity to present work in a friendlyand informal atmosphere, to meet other PhD-students from both schools, and to get acquainted with eachother’s work. PhD-students in their 1 st and 2 nd year will present their work as a poster, PhD-students in their3 rd year will present a blitz-presentation and a poster, and PhD-students in their 4 th year will give an oralpresentation.The two-day program includes research topics on both fundamental and clinical neuroscience. The meetingis also intended to learn how to present one’s work to a broad audience. In order to improve yourpresentation skills, there will be a short plenary evaluation of the presentations after each oral session. Inan attempt to get the best out of you, the best poster, the best blitz presentation and the best oralpresentation will be awarded. The best poster will be chosen by a ‘poster committee’, chaired by Prof. DopBär, whereas the best blitz-presentation and the best oral presentation will be chosen by the audience.Prizes will be awarded on Friday.We are pleased that the Nobel Prize laureate Prof. Bert Sakmann will give the Swammerdam Lecture“Microcircuits in the neocortex” on Thursday evening. Prof. Sakmann (1942) studied medicine andsubsequently did his doctorate work on the electrophysiological basis of pattern recognition at the KraepelinInstitute in Munich. He is currently the director of the Max-Planck-Institute for Medical Research inHeidelberg and head of the Department of Cell Physiology. In 1991 Prof. Sakmann and Prof. Erwin Neherwere awarded the Nobel Prize in Physiology and Medicine for “their discoveries concerning the function ofsingle ion channels in cells “. It is a great honor to have such a prestigious speaker at the 2006 PhDstudentmeeting.The organizers are grateful to the senior scientists who are coming to the meeting to guide the sessions.We hope that this PhD meeting in Woudschoten will give you a scientifically satisfactory exchange as wellas a pleasant stay.The organizing committee:Sanne BoesveldtHeleen BoosEls BorgholsElly HolGijs KooijMaurice MagnéeRogier MinEls MøstCharlotte OomenJeroen PasterkampValeria Ramaglia3

PROGRAM AND ABSTRACT BOOKAnnual MeetingGraduate School Neurosciences AmsterdamandRudolf Magnus Graduate School of NeuroscienceNovember 23 rd and 24 th , 2006Woudschoten Conference Center, ZeistGeneral information• Location of the meeting: Woudschoten Conference Center, Woudenbergseweg 54, Zeist.• You are expected to arrive on Thursday the 23 rd of November between 9.00 and 9.30 a.m. to allowsufficient time for registration and mounting of the posters.• Please note that the language of the meeting will be English.• During the meeting, staff members of the graduate school will provide feedback on the oralpresentations.• The size of the poster boards at Woudschoten is 1.20 m x 1.20 m.Public transport – transfer to and from WoudschotenOn Thursday morning at 9.15 a.m. a bus will be at train station Driebergen-Zeist to bring you – if you travelby public transport – to the conference center. At the end of the meeting a bus will go from the conferencecenter to the train station.Instructions for the poster sessionsAll posters will be mounted on the first day of the meeting and will remain on display during the entiremeeting. In this way the posters can be viewed during the whole meeting, also outside of the regular postersessions.Unlike last year, there will be no chaired poster discussions. Instead, 3 rd year PhD students are asked togive a short “blitz presentation” in which they can shortly summarize the data on their poster. Blitzpresentations should consist of a maximum of 2 slides, and take no more than 90 seconds. The time ofeach “blitz presentation” will be strictly monitored by the chairs and a member of the organizing committee.After 60 seconds the first alarm will sound, followed by a second and final alarm 30 seconds thereafter. Youwill have to directly stop with your presentation after the second alarm. Additionally there will be a postersession on each day. All poster and blitz presenters will be assigned a day and time during which they areexpected to stand at their poster and answer possible questions. To see at what time presenters can befound at their posters, please check the program.Instructions for oral presentersEach individual presentation is scheduled for maximal 15 minutes. Members of the organizing committeewill be present with an alarm clock to keep track of time. After 11 minutes the first alarm will sound, followedby a second and final alarm 1 minute thereafter. After this second alarm there are 3 more minutes fordiscussion. Since the meeting has a very tight schedule, we kindly ask you to not exceed the scheduledtime. Each session of four presentations will be followed by a didactic moment (feedback).Presentations will be given on a PC laptop using PowerPoint2003 and Windows XP.Presentations should be loaded onto this notebook during registration via CD or memory stick. Thereforepresenters scheduled for Thursday morning should plan to arrive early. All presenters should have a backupof their entire presentation (slides, figures, images) on a finalized CD or memory stick.Participants with files from a MAC environment should be sure to check their entire presentation in advanceon this computer to be sure that all animations and images appear as intended.The computer will be available during registration, coffee breaks, etc. Presenters with additional questionsor requiring sound should email e.hol@nin.knaw.nl.For questions about the program or the meeting, please contact Els Borghols, Graduate SchoolNeurosciences Amsterdam, tel. 020 – 598 6925, els@cncr.vu.nl5

Program Annual Meeting 2006Thursday, 23 November09.00 - 09.50 Registration / coffee and tea09.50 - 10.00 Words of welcome Rogier MinDidactic commentsChristiaan Levelt10.00 - 11.10 Brain imaging (page 18-21) chair: Hilleke Hulshoff PolFleur ZijlstraDopamine release and subjective craving in opioid addiction.Saskia WolfensbergerEvaluation of [ 11 C]R116301 as a potential PET ligand for investigating NK1 receptorsin human subjects.Jisca PeperQuantitative genetic modelling of brain volume in healthy (pre-) puberty: a twin study.Myriam VandenbrouckeA new approach to the study of visual detail processing in Autism Spectrum Disorder:investigating visual feedforward and feedback mechanisms.11.10 - 11.30 Printers market with coffee and tea11.30 - 12.40 Electrophysiology (page 22-25) chair: Nail BurnashevNeeltje van GemertEffects of chronic stress and acute corticosterone application on hippocampal calciumcurrents and gene expression.Rogier MinSuppression of inhibition by a direct action of cannabinoids on postsynaptic ionotropicGABA(A) receptors.Karlijn van AerdeDistinct fast network oscillations occur simultaneously in rat prefrontal cortex.Liviu StanisorThe effect of object-based learning in frontal eye field neurons.12.40 - 13.30 Lunch and printers market13.30 - 14.15 Blitz Session I chair: Christiaan Levelt14.15 - 15.45 Poster Session (page 43-91, alphabetially) / Printers market15.45 - 16.30 Printers market / free time16.30 - 17.40 Neurodegeneration and regeneration (page 26-29) chair: Joost VerhaagenTam VoA role of semaphorin 3a in the disassembly of neuromuscular junctions in the G93AhSOD1mouse, a model for amyotrophic lateral sclerosis?Martijn TannemaatGenetic modification of human sural nerve segments by a lentiviral vector encoding nervegrowth factor.Valeria RamagliaComplement inhibition facilitates regeneration of the injured peripheral nerve.Jose SaavedraGeneration of conditionally immortalized mouse Schwann cells from a PMP22overexpressing mouse: Unraveling the molecular mechanisms of inheritedneuropathies.18.00 - 20.00 Dinner20.00 - 21.00 Swammerdam Lecture (page 17) Microcircuits in the neocortex.Prof.dr. Bert Sakmann from Max Planck Institute, Heidelberg, Germany.6

Program Annual Meeting 2006Friday, 24 November08.30 - 09.30 BreakfastDidactic commentsMatthijs Verhage09.30 - 10.40 Behavior (page 30-33) chair: Martien KasFloor RemmersExpression of energy balance regulation peptides in juvenile and adult rathypothalamus after early postnatal food restriction.Krista WilleboerParametric cochlear implant fitting adjustments by recipients.Leonie de VisserHome sweet home: contribution of automated home cage observations to behaviouralgenetics.Maarten LoosDissecting anxiety and impulsivity at a behavioral and genomic level.10.40 - 11.00 Coffee and tea11.00 - 12.10 Hippocampus (page 34-37) chair: Paul LucassenOlof WiegertThe effect of corticosterone on AMPA receptor subunit localisation and its effect onhippocampal synaptic efficiency.Tim HeistekGABA A receptor functioning in hippocampal fast network oscillations.Erwin van VlietBlood-brain barrier leakage may lead to progression of temporal lobe epilepsy.Heleen BoosBrain volumes in relatives of patients with schizophrenia: a meta-analysis.12.10 - 13.00 Lunch13.00 - 13.45 Blitz Session II chair: Matthijs Verhage13.45 - 15.15 Poster Session (page 43-91, alphabetically)15.15 - 16.35 Schizophrenia and Alzheimer (page 38-42) chair: Neeltje van HarenRachel BransBrain volume changes in monozygotic and dizygotic twins discordant forschizophrenia: a 5-year longitudinal MRI study.Maartje AukesGenetics of schizophrenia: segregation analysis of endophenotypes.Janneke ZinkstokThe COMT val 158 met polymorphism and brain morphometry in healthy young adults.Sidhartha ChafekarThe role of the aggregation state of Amyloid-β on its neurotoxicity.Koen BossersIdentification of transcriptional alterations in human postmortem brains of Parkinson’sDisease and Alzheimer’s Disease.16.35 - 16.45 Poster Award Dop Bär16.45 - 16.55 Blitz and Oral Presentation Award16.55 - 17.00 Closing remarks Rogier Min7

Blitz Session I 23 November, 13.30 - 14.15chair: Christiaan Levelt47 Annelies WesterEvent-related potentials and secondary task reformance during simulated driving.25 Eunjeong LeeFiring activity in the rat medial prefrontal cortex during changes in stimulus relevance.27 Maurice MagnéeCrossmodal integration of emotional faces and voices in Pervasive Developmental Disorder:an ERP study.1 Ellemarije AltenaImaging prefrontal consequences of chronic insomnia: results of two verbal fluency tasks anda set shifting task in fMRI.33 Hilde NederveenA longitudinal structural MRI-study of adolescence in high-functioning autism spectrumdisorders: preliminary evidence of progressive change.22 Imke van KootenCytoarchitectonic abnormalities in the temporal fusiform gyrus in autistic patients.36 Heval OzgenNormal values for phenotypic abnormalities in school children.41 Mirjam SprongDutch prediction of psychosis study: parameters of social functioning in adolescents at highrisk of psychosis.6 Geartsje BoonstraDoes brain volume change after withdrawal of antipsychotic medication in first-episodeschizophrenia?19 Jeroen KoningInstrumental assessment of tongue dyskinesia.15 Daniel van GrootheestAssortative mating for obsessive-compulsive behavior in a population-based sample.18 Hilga KaterbergMutation screening of the SCGE gene in Obsessive-Compulsive Disorder and Tourettesyndrome.5 Sanne BoesveldtOlfactory testing in Dutch Parkinson’s disease patients.23 Hilde KrolContribution of polyglutamine expansion to Ataxin-1 foci formation.8

Blitz Session II 24 November, 13.00 - 13.45chair: Matthijs Verhage26 Harold Mac GillavryThe role of the transcription factor Nfil3/E4BP4 in neuronal regeneration.7 Meg BreuerLong-term behavioral changes after cessation of chronic antidepressant treatment in olfactorybulbectomized rats.45 Linda VerhagenInvolvement of dopamine metabolism in rats exposed to activity-based anorexia.49 Maqsood YaqubQuantification of dopamine transporter binding using [ 18 F]FP-β-CIT and positron emissiontomography.30 Annetrude de MooijFinding genes involved in avoidance and approach behaviour using chromosome substitutionstrains.34 Michel van den OeverMolecular plasticity at the synapse resulting from heroin abstinence and reinstatement ofheroin seeking behavior.13 Elly van GalenDistinct behavioral and structural brain abnormalities in αPix/Arhgef6- deficient mice.38 Zhenwei PuCorticosterone time-dependently modulates beta-adrenergic effects on LTP in hippocampaldentate gyrus.48 Marijn van WingerdenEffects of NMDA receptor activity on in vivo firing patterns of single units in orbitofrontal cortexof awake male Wistar rats.12 Jeroen DudokRaphe nucleus organotypic slice culture to study the serotonergic connectivity ex vivo.40 Hadi SaiepourRole of β-catenin in visual plasticity.39 Monica RaisCannabis use and gray matter volume in schizophrenia: a five-year longitudinal MRI study.16 Saskia van der HelHippocampal changes in the juvenile pilocarpine model of temporal lobe epilepsy.42 Niels van StrienConvergence of parallel sensory information processing routes in the rat parahippocampalregion.9

Poster Session 23 November, 14.15-15.45discussion with poster presenters: 23 November, 14.15-14.451 Ellemarije AltenaImaging prefrontal consequences of chronic insomnia: results of two verbal fluency tasks anda set shifting task in fMRI.2 Marijke de BackerObese rats by lentiviral-mediated transgenesis.3 Karin BoerRecent development in the molecular pathogenesis of hemimegalencephaly in patients withintractable epilepsy.4 Marieke de BoerNeural coding of attentional processes in mouse prefrontal cortex.5 Sanne BoesveldtOlfactory testing in Dutch Parkinson’s disease patients.6 Geartsje BoonstraDoes brain volume change after withdrawal of antipsychotic medication in first-episodeschizophrenia?7 Meg BreuerLong-term behavioral changes after cessation of chronic antidepressant treatment in olfactorybulbectomized rats.8 Jurjen BroekeThe role of neurotransmitter secretion during axon outgrowth on growth cone dynamics.9 Cathrin CantoNeuron diversity in the medial entorhinal cortex of the rat.discussion with poster presenters: 23 November, 14.45-15.1510 Danielle CounotteAdolescent nicotine exposure impairs performance in a visuospatial attention task duringadulthood.11 Nienke DekkerCessation of cannabis use in patients with recent-onset schizophrenia.12 Jeroen DudokRaphe nucleus organotypic slice culture to study the serotonergic connectivity ex vivo.13 Elly van GalenDistinct behavioral and structural brain abnormalities in αPix/Arhgef6- deficient mice.14 Judith GillisMimicking intracellular protein aggregation using a peptide-based approach.15 Daniel van GrootheestAssortative mating for obsessive-compulsive behavior in a population-based sample.16 Saskia van der HelHippocampal changes in the juvenile pilocarpine model of temporal lobe epilepsy.17 Ellen HesselSusceptibility genes for sporadic febrile seizures.18 Hilga KaterbergMutation screening of the SCGE gene in Obsessive-Compulsive Disorder and Tourettesyndrome.10

discussion with poster presenters: 23 November, 15.15-15.4519 Jeroen KoningInstrumental assessment of tongue dyskinesia.20 Gijs KooijSuperoxide disorganizes brain endothelial cytoskeleton via PI 3-kinase.21 Cédric KoolschijnHypothalamic abnormalities and genetic risk in twins discordant for schizophrenia.22 Imke van KootenCytoarchitectonic abnormalities in the temporal fusiform gyrus in autistic patients.23 Hilde KrolContribution of polyglutamine expansion to Ataxin-1 foci formation.24 Marieke LangenCaudate nucleus is enlarged in high-functioning medication-naive subjects with autism.25 Eunjeong LeeFiring activity in the rat medial prefrontal cortex during changes in stimulus relevance.26 Harold Mac GillavryThe role of the transcription factor Nfil3/E4BP4 in neuronal regeneration.Poster Session 24 November, 13.45-15.15discussion with poster presenters: 24 November, 13.45-14.1527 Maurice MagnéeCrossmodal integration of emotional faces and voices in Pervasive Developmental Disorder:an ERP study.28 Joost MeekesEpilepsy surgery in children: imaging plasticity of memory.29 Jinte MiddeldorpGFAP isoforms in brains of Alzheimer patients and non-demented controls.30 Annetrude de MooijFinding genes involved in avoidance and approach behaviour using chromosome substitutionstrains.31 Els MøstPrevention of depression and sleep-disturbances in elderly with memory-problems; activationof the biological clock with light.32 Martijn MulderGenetic risk for ADHD in brain functioning.33 Hilde NederveenA longitudinal structural MRI-study of adolescence in high-functioning autism spectrumdisorders: preliminary evidence of progressive change.34 Michel van den OeverMolecular plasticity at the synapse resulting from heroin abstinence and reinstatement ofheroin seeking behavior.35 Charlotte OomenBrief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the chronicstress-induced reduction of adult hippocampal neurogenesis.11

discussion with poster presenters: 24 November, 14.15-14.4536 Heval OzgenNormal values for phenotypic abnormalities in school children.37 Jasper PoortNoise correlations can help or hinder discrimination in V1.38 Zhenwei PuCorticosterone time-dependently modulates beta-adrenergic effects on LTP in hippocampaldentate gyrus.39 Monica RaisCannabis use and gray matter volume in schizophrenia: a five-year longitudinal MRI study.40 Hadi SaiepourRole of β-catenin in visual plasticity.41 Mirjam SprongDutch prediction of psychosis study: parameters of social functioning in adolescents at highrisk of psychosis.42 Niels van StrienConvergence of parallel sensory information processing routes in the rat parahippocampalregion.43 Maartje VeenemanA parametric evaluation of models to measure the motivational properties of cocaine in rats.discussion with poster presenters: 23 November, 14.45-15.1544 Elly VereykenA model for specific de- and remyelination in rodent whole brain spheroid cultures.45 Linda VerhagenInvolvement of dopamine metabolism in rats exposed to activity-based anorexia.46 Elizabeth WansinkCholinergic and dopaminergic interaction at the corticostriatal synapse in Parkinson’s disease.47 Annelies WesterEvent-related potentials and secondary task reformance during simulated driving.48 Marijn van WingerdenEffects of NMDA receptor activity on in vivo firing patterns of single units in orbitofrontal cortexof awake male Wistar rats.49 Maqsood YaqubQuantification of dopamine transporter binding using [ 18 F]FP-β-CIT and positron emissiontomography.50 Yeping ZhouUnraveling the intracellular signal transduction mechanisms that underlie axon guidance:MICALs lead the way.12

Instructions for making a poster1. Planning a posterWhen planning to make a poster, the main factor to be considered is the amount of information. As postersessions are often located in badly illuminated and noisy halls, limitation to as few messages as possible iscrucial. During the session, you will be present to answer questions and give additional information.Since posters are normally displayed for longer than one session, the essential points should be selfexplanatory.2. Poster instructionsRead the poster instructions carefully before starting. Meeting organizers provide detailed information aboutsize, location, length of the session etc.On this meeting, the size of your poster should be 1.20 m x 1.20 m.3. Poster lay-outStart with making a rough lay-out, in which you plan the approximate position of figures and text. At thisstage the number of figures and the amount of text are determined.Organize the poster in sections, divided over columns which may be read from the top left corner to thebottom right one. Sections must be indicated by separate headings, and preferably by numbers or letters toaid reading in sequence.4. TitleA brief, informative, and (if possible) provocative title will attract viewer’s interest most effectively. A title ofthree lines is generally too long and, together with the names of the authors and the institution, will take uptoo much space. Letter height should be at least 2.5 cm.5. IntroductionThe introduction should state the background and main question(s) addressed in the poster. The sentencesused for such statements should be short and simple, offering the main points to the reader at a glance.Letter height should be around 0.85 cm (24 point or larger) in order to be read from a distance of 1-2meters.6. FiguresAs figures illustrate the main points in a poster they are much faster to “read” than words. Therefore, usefigures to tell the story and plan the poster around the figures. Use figures not only to present the results,but (if possible) also the methods used.Graphs must be large (at least 21 x 28 cm). Axis labels should not be less than 24 points. Colored graphspresent information better. Figures should be numbered clearly (bold lettering). A short legend underneatheach figure should provide essential information from the figure, including details left out in the figure itself.7. ConclusionsThe conclusions are often presented in the right bottom corner of the poster. The top right corner might beconsidered for very busy congresses (viewers in the second or third row may then still be able to read itover the shoulders of viewers in front).The conclusion section should summarize the main points in short statements. Letter size should differ fromthat used for results and be at least 24 points.8. Poster production and colorTake care that you reserve enough time to prepare a poster. Think more in terms of days than in hours!Since poster boards are often white or a neutral color, a colored background covering the entire posterspace is preferable. However, take care that the color(s) used do not overrule the message of the poster.13

Tips for an oral presentation (see also www.onwa.med.vu.nl)1. Wear unobtrusive clothes.2. Start with general remarks (who you are, in what group you are working, what the subject is of yourproject) so that the audience will have a chance to get used to your voice.3. Try to tell your story in ordinary, simple words, write out the text, and delete "article' sentences" earlyon.4. Structure the talk so that at all times the audience knows what section you have reached. Mention thestructure of your presentation, clearly round each section off, and return to the overall structure beforegoing on to the next section. Present conclusions per section on a slide or sheet as well as in speech.5. Structure the contents from general knowledge to specific knowledge, and then to your latestcontributions, and not vice versa!6. Describe experiments in a chronological order.7. Illustrations and conclusions must be balanced: present more slides with conclusions rather thatshowing many slides with controls. The audience takes it for granted that the experimental approachwill have been sound, including sufficient controls.8. Slides: size and contrast of the lettering is of great importance.Use colour selectively: black letters of a suitable size on a light (white) background are easy to readfrom all corners of a lecture room of average size, but (for instance) yellow letters on a blackbackground are much less readable. And it is virtually impossible to distinguish between threedifferent shades of yellow on a light green background.Do not use too many different colours as background in the slides within one presentation. It distractsfrom the data when one slides has a background of light yellow, the next a white background, the thirdblack or brown with fluorescent letters, and so on.9. Sheets: when writing by hand use a ruler to keep the liens straight Keep the margins wide, especiallywhen presenting tables.10. When the lettering is not big enough to read from the back of the lecture hall, it helps the audienceseated there to follow the story if you read the text in figures and tables.11. If there is enough room, change the place where you stand, to the left or right of the projectedillustrations.12. If a presentation may be 15 or 25 minutes, tell the story in 10 or 20 minutes respectively, so that thereis ample time for discussion (or to allow for a later start). Practise!G.E.E. van Noppen/199914

ABSTRACTSSwammerdam Lecture prof.dr. B. SakmannFor oral presentations: in order of presentationFor poster presentations: in alphabetical order15

SWAMMERDAM LECTURETITLEMICROCIRCUITS IN THE NEOCORTEXAUTHORBert SakmannDEPARTMENT/INSTITUTECell Physiology, Max-Planck-Institute For Medical Research, Heidelberg, GermanyABSTRACTBasic neuroscience aims at elucidating the neuronal code by which nerve cells communicate and themechanisms of plasticity of the brain. These phenomena are known to generate higher brain functions suchas recognizing the environment, initiate movements and learning to adapt to a new environment. Higherbrain functions are dependent on the intact neocortex, also known as the grey matter that covers the brainof all vertebrates. The elucidation of basic cortical mechanisms may help to understand, at a cellular andeven molecular level, the causes of neurological disorders.The surface of the cerebral cortex in mammals is divided into a landscape of "cortical maps". These mapsassign the representation of a particular cortical function to a particular area of the brain. To understand interms of the cellular anatomy and electrical signals of the nerve cells, the representation of sensory stimulior of motor programs one has to take into account the laminar structure of the cortex. The cortex is dividedinto cortical layers numbered from 1 to 6 from pia to white matter. Each of the layers presumably subservesdifferent functions in representation and output to other cortical areas.We have used whole-cell recording of electrical activity from anatomically identified and subsequentlyreconstructed pairs of cells, voltage sensitive dye (VSD) imaging of the activity of ensembles of cells inlayer 2/3 and finally two photon (2p) excitation imaging of an ensemble of cells in layer 2/3 at cellularresolution.The results indicate that feature representation i.e. of a simple peripheral stimulus is both time and layerdependent. The most active layer is layer 5B, the least active layers are L5A and L2/3. In all layers,however, the neuronal code is sparse, meaning that only small percentage of cells in each layer isgenerating APs. Nevertheless few APs in a single column can drive a complex behavioural response to asensory stimulus.KEY WORDS: Cortex layer, microcircuits, VSD-imagingTELEPHONE-NUMBER: +49 (0)6221 486461E-MAIL-ADDRESS: zpsecr@mpimf-heidelberg.mpg.de17

TITLEDOPAMINE RELEASE AND SUBJECTIVE CRAVING IN OPIOID ADDICTIONAUTHORFleur ZijlstraDEPARTMENT/INSTITUTEDepartment of Nuclear Medicine, Academic Medical Centre, University of Amsterdam & AmsterdamInstitute for Addiction ResearchABSTRACTIntroductionA two-way model (Pilla et al., 1999) further extended by by Childress and O’Brien (Childress & O'Brien,2000) suggests that two mechanisms are involved in addictive processes. According to this model, cravingin drug dependent subjects may be the result from both chronic low dopaminergic activity, as representedby low dopamine D2 receptor availability in the striatum, and a temporary enhanced cue-eliciteddopaminergic activity in the striatum, amygdala and anterior cingulate cortex (ACC). This model will betested in humans using Single Positron Emission Tomography (SPECT).MethodIn the present study 14 abstinent male opiate users and 18 healthy comparison subjects were included.The control subjects were group matched on gender, age, and smoking status. Each subject underwentSPECT scanning to assess baseline dopamine D2 receptor levels and dopamine release using a cueinducedcraving paradigm. These studies were performed using a 12-detector single slice tomographicdedicated brain SPECT camera. Craving measures were acquired using a the Desires for Drug UseQuestionnaire (DDQ) and the Snaith-Hamilton Anhedonia Scale (SHAPS).ResultsWe did not find a significant difference in uptake ratio between opiate dependant subjects and controls.Neither did we find a difference of endogenous dopamine release between both groups. We did find thescores on the DDQ desire 1 subscale to correlate with the dopamine release. We also did find the ‘desire’and ‘negative reinforcement’ scales to interact with dopamine release in the left striatum and in lesserdegree in the right striatum. Additionally, an inverse correlation between dopamine release in the striatumand anhedonia was apparent. We found that dopamine release in the left striatum correlated with ameasure for anhedonia depicted by the scores of the SHAPS. No such relation was found the controlsubjects.ConclusionThere seems to be no significant difference in baseline D2 receptor availability between heroin addictedindividuals and smoking healthy controls. However, there is a clear relation between craving for drugs anddopamine release in the left striatum showing that the higher the measure for dopamine release is, theincrease in subjective craving .KEY WORDS: Addiction, dopamine, D2 receptor, PET, SPECTTELEPHONE-NUMBER: 020-5664309E-MAIL ADDRESS: c.zijlstra@amc.uva.nl18

TITLEEVALUATION OF [ 11 C]R116301 AS A POTENTIAL PET LIGAND FOR INVESTIGATING NK1RECEPTORS IN HUMAN SUBJECTSAUTHORSSaskia P.A. Wolfensberger, Anu J. Araiksinen, Bart N.M. van Berckel, Ronald Boellaard, William D.H.Carey, Wieb Reddingius, Dick J. Veltman, Bert D. Windhorst, Josée E. Leysen, Adriaan A. LammertsmaDEPARTMENTDepartment of Nuclear Medicine & PET Research and Psychiatry, VU University Medical Center, TheNetherlands, Johnson & Johnson Pharmaceutical Research & Development, Beerse, BelgiumABSTRACTR116301 is an orally active, potent and selective non-peptide NK1 receptor antagonist with a K i of 0.45 nMagainst human NK1 receptors. The binding affinity of R116301 for human NK2 and NK3 receptors is 1600and 230 fold lower, respectively. R116301 suppresses various aspects of substance P (SP) inducedbehaviour in vivo and behaves as a full antagonist in vitro. SP mediates fear responses and anxiety, andprobably has a role in sensation of visceral pain. Positron Emission Tomography (PET), using a NK1receptor ligand, may help to relate brain NK1 receptor occupancy to clinical effects and to understandchanges in NK1 receptor population density during disease.ObjectiveThe objective of this pilot study was to evaluate [ 11 C]R116301 as a potential PET ligand for investigatingNK1 receptors in vivo.MethodsPET studies were performed in 3 normal controls. Each PET session consisted of 2 [ 11 C]R116301 scans, 5hours apart. Exactly 3.5 hours before the second scan, a single oral (blocking) dose of 125 mg aprepitant(EMEND) was given.Individual scan sessions consisted of a transmission scan and a dynamic emission scan followingintravenous administration of ~370 MBq [ 11 C]R116301. The 3D emission scan consisted of 23 frames withprogressive increase in frame duration and a total scan duration of 90 minutes. In addition, using on-linedetection and discrete manual samples, a metabolite corrected arterial plasma input function was derived.For each subject, both pre- and post-aprepitant scans were co-registered to the corresponding individualMRI. Regions of interest (ROI) were defined on the MRI scans and projected onto both co-registered PETscans to generate tissue time-activity curves (TAC). Whole striatum was used as the structure with thehighest density of NK1 receptors, and cerebellum as reference tissue.Scan data were analysed using arterial input compartment models, reference tissue models and simplestriatum to cerebellum ratios.ResultsEquilibrium was reached relatively early after injection, and striatum to cerebellum ratios were almostidentical for the intervals 20-90 and 60-90 minutes. Following aprepitant administration these ratiosdecreased 63, 51 and 20% relative to the corresponding baseline data. Compartmental analysis was notpossible as arterial input curves were distorted due to significant sticking of [ 11 C]R116301 to the wall of thePTFE tubing. Reference tissue models showed a major reduction in binding potential (BP) due to aprepitantadministration, but standard errors of baseline BP were too high for reliable quantification.ConclusionThese preliminary results indicate that [ 11 C]R116301 has potential as a radioligand for in vivo assessmentof NK1 receptors in the human brain. Further studies are required for developing a reliable quantitativemethod.KEY WORDS: NK1 receptor, R116301, PETTELEPHONE-NUMBER: 020-4441728E-MAIL ADDRESS: spa.wolfensberger@vumc.nl19

TITLEQUANTITATIVE GENETIC MODELLING OF BRAIN VOLUME IN HEALTHY (PRE-) PUBERTY: A TWINSTUDYAUTHORSJisca S. Peper 1 , R.S. Kahn 1 , M. van Leeuwen 2 , C. van Baal 1 , H.G. Schnack 1 , D.I Boomsma 2 , H.E.Hulshoff Pol 1 .DEPARTMENT/INSTITUTE1 University Medical Center Utrecht, 2 Free University AmsterdamABSTRACTBackgroundHuman puberty is an important period during development. Besides cognitive and endocrinologicalchanges, brain structure is showing developmental changes. During puberty, overall grey matter slowlystarts to decrease in volume, whereas white matter volume is still increasing. However, the relativeinfluences of genetic and environmental factors on these developmental brain changes around the onset ofpuberty is not known.Aim and MethodIn this study, the contribution of genetic and environmental factors to individual variation in human brainvolume during puberty was determined. Subjects are 303 healthy children coming from 107 twin-families inthe Netherlands, including 45 monozygotic, 62 dizygotic twin-pairs of 9 years old and 88 full siblingsbetween 9 and 14 years of age. Structural magnetic resonance imaging (MRI) brain scans were made on a1.5 T Achiva Philips System. Semi-automatic image processing was used for measuring intracranialvolume, total brain, gray and white matter, cerebellum and lateral and third ventricle volumes. Pubertalstatus was determined by the Tanner questionnaire. Gonadal hormone secretion was determined in salivasamples. Data were statistically analyzed using structural equation modelling using Mx-software.ResultsThe results will be discussed during the Annual Meeting.KEY WORDS: Brain volume, heritability, puberty, twinsTELEPHONE-NUMBER: 030-2507549E-MAIL-ADDRESS: j.s.peper@umcutrecht.nl20

TITLEA NEW APPROACH TO THE STUDY OF VISUAL DETAIL PROCESSING IN AUTISM SPECTRUMDISORDER: INVESTIGATING VISUAL FEEDFORWARD AND FEEDBACK MECHANISMSAUTHORSMyriam W.G. Vandenbroucke, H.Steven Scholte, H. van Engeland, V.A.F. Lamme, C. KemnerDEPARTMENT/INSTITUTEDepartment of Youth and Adolescent Psychiatry (UMCU) / Department of Psychology (UvA)ABSTRACTAutism Spectrum Disorder (ASD) is described by several behavioural abnormalities, including a strongtendency for detail perception. However, as yet, there is no neurobiological explanation for this aspect ofASD. In the current paper, a clarification for increased visual detail processing is proposed and investigatedbased on insights in the role of feedforward and feedback activity in visual perception. As visual inputenters the cortex in V1 elementary features are detected. The input travels to higher visual areas, whereneurons have larger receptive fields and global aspects are extracted. This so-called feedforwardprocessing is influenced by the output of horizontal connections, introducing the detection of edges. Duringfeedforward processing, higher visual areas start communicating with lower visual areas, by means offeedback pathways. This leads to the integration and implementation of low-level features. An imbalancebetween feedforward, horizontal and feedback connections could cause an imbalance between global anddetail processing. If, for example, feedback activity is stronger compared to feedforward, this will lead to anoverrepresentation of details in a visual scene. We conjectured that the latter situation is the case in ASD.We used both psychophysical and EEG data from a texture discrimination task to test this hypothesis.Good performance in the task strongly relied on feedback processing and subtraction ERP’s coulddistinguish between feedforward, horizontal and feedback activity.The results showed that, initially, subjects with ASD (N = 13) had lower performance scores compared tocontrols (N = 31) and the psychophysical data indicated stronger feedback processing in the patient group.However, the EEG data of a second and third measurement showed that there was an initial problem inhorizontal connection activity, which influenced the consecutive visual mechanisms, i.e. the strength offurther feedforward processing and the latency of feedback activity.From the current results we can conclude that aberrancies in early, low-level visual mechanisms (i.e. lateralinhibition by horizontal connections) in subjects with ASD lead to an imbalance between feedforward andfeedback processing. This might be the underlying cause of excessive detail processing in these patients.KEY WORDS: Autism, detail, global, horizontal connections, EEGTELEPHONE-NUMBER: 020-5256741E-MAIL-ADDRESS: m.w.g.vandenbroucke@uva.nl21

TITLEEFFECTS OF CHRONIC STRESS AND ACUTE CORTICOSTERONE APPLICATION ONHIPPOCAMPAL CALCIUM CURRENTS AND GENE EXPRESSIONAUTHORSNeeltje G. van Gemert 1 , Henk Karst 1 , Onno C. Meijer 2 and Marian Joëls 1DEPARTMENT/INSTITUTE1Swammerdam Institute for Life Sciences, Center for NeuroScience, University of Amsterdam, Amsterdam2Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research and Leiden UniversityMedical Center, LeidenABSTRACTStress is an important risk factor for various neurological and psychiatric illnesses. In response to stress,the adrenal hormone corticosterone is released and enters the brain where it affects cell functioning invarious brain areas, including the hippocampus.To get more insight in brain processes affected by chronic stress, we studied hippocampal cell functionunder such circumstances in an animal model. In rats subjected to a 21-day chronic unpredictable stressparadigm, disturbances of various processes in the hippocampus have been reported; among other things,altered expression of various calcium channel subunits in the dentate gyrus has been found. We recordedcalcium currents from hippocampal dentate granule cells in vitro using the whole cell patch clamptechnique. Data indicate that the functional properties of calcium currents show a similar stress dependencyas the expression of the calcium channel subunits.Interestingly, chronic stress affected calcium currents differently in the hippocampal CA1 area whencompared to the dentate gyrus. Additional experiments revealed that acute application of a high dose ofcorticosterone resulted in increased calcium currents in the CA1 area, whereas calcium currents recordedfrom dentate granule cells were not affected. To get more insight in the mechanisms responsible for thisdifferential effect, we currently study the influence of corticosterone on mRNA expression of various calciumchannel subunits in both hippocampal areas.KEY WORDS: Chronic stress, corticosterone, calcium current, CA1 area, dentate gyrus, gene expressionTELEPHONE-NUMBER: 020-5257719E-MAIL-ADDRESS: nvgemert@science.uva.nl22

TITLESUPPRESSION OF INHIBITION BY A DIRECT ACTION OF CANNABINOIDS ON POSTSYNAPTICIONOTROPIC GABA(A) RECEPTORSAUTHORSRogier Min 1 , Tatjana Golovko 2 , Natalia Yatsenko 3 , Natalia Lozovaya 3 , Volker Mack 2 , Andrei Rozov 2 andNail Burnashev 1DEPARTMENT/INSTITUTE1 Department of Experimental Neurophysiology, Center for Neurogenomics and Cognitive Research(CNCR), Vrije Universiteit Amsterdam, Amsterdam. 2 Department of Clinical Neurobiology, UniversityHospital for Neurology, University of Heidelberg, Germany.3 Department of Cellular Membranology, Bogomoletz Institute of Physiology, UkraineABSTRACTMost of the effects of cannabinoids on mammalian behaviour are attributed to activation of G-proteincoupledcannabinoid CB1 receptors (CB1Rs), which are abundantly expressed throughout the brain.Activity dependent synthesis and retrograde release of endogenous cannabinoids can reduce the strengthof inhibitory synapses through activation of presynaptic CB1Rs. However, cannabinoids affect behaviourboth in the presence of CB1R antagonists and in CB1R knockout mice. This suggests that additional braintargets for cannabinoids exist. Here we report that cannabinoids can modulate inhibitory synaptictransmission independent of CB1R activation by a direct modulation of postsynaptic GABA(A) receptors(GABA(A)Rs). Cannabinoids reduce the amplitude and modulate the kinetics of GABA(A)R mediatedcurrents in HEK293 cells expressing recombinant GABA(A)Rs, as well as in isolated hippocampalpyramidal neurons. Paired recordings from rat neocortical slices confirm these observations in functionalsynapses, and show that release of endogenous cannabinoids can also lead to a postsynaptic modulationof GABA(A)R mediated IPSCs. At the microcircuit level, CB1R independent modulation of GABA(A)Rsreduces the influence of GABAergic interneurons on the firing of neocortical pyramidal neurons. Theseresults show the existence of a CB1R independent action of cannabinoids directly on postsynapticGABA(A)Rs, representing a novel mechanism by which neurons can regulate synaptic inhibition.KEY WORDS: GABA(A) receptors; cannabinoids; synaptic transmissionTELEPHONE-NUMBER: 020-5987099E-MAIL-ADDRESS: rogier.min@cncr.vu.nl23

TITLEDISTINCT FAST NETWORK OSCILLATIONS OCCUR SIMULTANEOUSLY IN RAT PREFRONTALCORTEXAUTHORSKarlijn I. van Aerde*, C.B. Canto***, E.O. Mann**, A.B. Brussaard*, O. Paulsen**, H.D. Mansvelder*DEPARTMENT/INSTITUTE* Dept of Experimental Neurophysiology, Center for Neurogenomics and Cognitive Research (CNCR), VrijeUniv. Amsterdam. ** Neuronal Oscillations Group, Dept of Physiology, Univ. of Oxford, UK.*** Dept. of Anatomy and Neurosciences, VU University medical center, AmsterdamABSTRACTThe prefrontal cortex (PFC) of rodents consists of multiple areas distributed over the forebrain. The medialPFC of rodents includes the prelimbic and infralimbic areas. Both are involved in attention and goal directedbehavior that depend on acetylcholinergic signaling, but have distinct roles in these processes. In EEGrecordings, oscillations in the gamma frequency band (30-90 Hz) associated with attention and workingmemory occur in the PFC. Our aim was to identify conditions under which gamma-band oscillations occurin the PFC network in vitro and investigate underlying mechanisms using single cell recordings. Bathapplication of muscarinic acetylcholine receptor agonist carbachol induced oscillations that were blocked byatropine, bicuculline or AMPA/kainate-R blocker DNQX. Comparing fast network oscillations in prelimbicand infralimbic areas revealed that both areas had distinct oscillation frequencies and power. When bothareas were separated, infralimbic PFC remained oscillating with larger power and at an higher frequencythan prelimbic PFC, suggesting endogenous differences exist between these cortical networks.In prelimbic PFC, oscillations were most prominent in deep layers. Cross-correlation analysis revealed aphase reversal of oscillations between deep and superficial layers. In a proportion of slices two frequencycomponents could be observed. The higher frequency oscillation was more prominent in superficial layer 5,whereas the lower frequency oscillation showed the highest power in deep layer 5/layer 6. Single cellrecordings from layer 5 pyramidal cells showed that in the majority of cells action potential firing was phaselockedto the field oscillations. In cases of two simultaneous fast network oscillations some layer 5pyramidal cells showed phase-locking to both oscillations, but others showed only phase-locking behaviorto the higher frequency oscillation in superficial layer 5.In conclusion our results suggest that in rodent PFC acetylcholingergic agonists induce multiple distinct fastnetwork oscillations that are driven by distinct neuronal networks.KEY WORDS: Fast network oscillations, prefrontal cortex, working memory/attentionTELEPHONE-NUMBER: 020-598 7032E-MAIL-ADDRESS: karlijn@cncr.vu.nl24

TITLETHE EFFECT OF OBJECT-BASED LEARNING IN FRONTAL EYE FIELD NEURONSAUTHORSLiviu Stănişor and Arezoo PooresmaeiliDEPARTMENT/INSTITUTEVision and Cognition, Netherlands Institute for Neurosciences, KNAW, AmsterdamABSTRACTIn everyday life, continuous learning is essential in establishing connections between new stimuli and thosestored in memory. Neurons in area FEF (Frontal Eye Field) together with SEF (Supplementary Eye Field)have been shown to be involved in generating goal-directed but not spontaneous saccades. There is apopulation of cells called learning-dependent (Chen & Wise 1995), which show increased activity(modulation) as learning progresses from novel stimuli to familiar ones. Our aim is to investigate in asystematic manner how this activity evolves during associative learning. We will achieve this goal byrecording the electrical activity of learning-dependent neurons in FEF (single-unit recording) in macaquemonkeys.KEY WORDS: Macaque monkey, FEF, learning, modulation, single unitsTELEPHONE-NUMBER: 020-5664799E-MAIL-ADDRESS: l.stanisor@nin.knaw.nl25

TITLEA ROLE OF SEMAPHORIN 3A IN THE DISASSEMBLY OF NEUROMUSCULAR JUNCTIONS IN THEG93A-hSOD1 MOUSE, A MODEL FOR AMYOTROPHIC LATERAL SCLEROSIS?AUTHORSTam Vo, F. de Winter, E.M.E. Ehlert, S.P. Niclou, F.L. van Muiswinkel*, J. VerhaagenDEPARTMENT/INSTITUTEDept of Neuroregeneration, Netherlands Institute for Brain Research, Amsterdam; * Rudolf Magnus Instituteof Neuroscience, Dept of Neurology, University Medical Centre Utrecht, UtrechtABSTRACTAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by death ofmotoneurons and retraction of their synapses from the neuromuscular junction (NMJ) resulting in loss offunction of the motor unit. Although the sequence of events and the disease mechanism are largelyunknown, recent data from transgenic mouse models showed that the environment surroundingmotoneurons plays a crucial role. The best studied mouse model for ALS is the G93A-hSOD1 mouse,overexpressing a mutant version of the human superoxide dismutase 1 (hSOD1) gene. In this model, like inhuman patients, degeneration of the NMJ starts on muscle fiber type IIb/x. NMJs on this muscle fiber typeare ‘non-plastic’ in several denervation paradigms. We have studied the expression of the chemorepulsiveguidance protein semaphorin 3A (sema3A) in the G93A-hSOD1 mouse. Our results indicate that thischemorepellent axon guidance molecule is specifically expressed at NMJs on muscle fiber type IIb in 12and 18 week G93A-hSOD1 mouse. Based on co-localization with S-100 we conclude that Sema3A mRNAand protein expression was observed in the terminal Schwann cells and not in the myelinating Schwanncells in the muscle. We hypothesize that Sema3A may induce degeneration of or contribute to thedisassembly of NMJs at type IIb muscle fibers in G93A-hSOD1 mice.As a first step to determine a possible role for Sema3A in the induction of the loss of motor function in theG93A-hSOD1 mouse, we currently investigate the time course of the disease progression in relation to theinduction of sema3A in TSC in mice that are 5, 6, 7, 8, 10, 12, 14, 16 and 18 weeks of age. We found thatsema3A is already highly expressed at 5 weeks on muscle fiber type IIb/x. Studying the expression ofsema3A in relation the integrity of the neuromuscular synapse will be achieved by co-immunostaining withsynaptic vesicle marker, neurofilament antibodies and bungarotoxin. A possible relationship betweensema3A and motor neuron degeneration will be studied by conditional knock out of sema3A or its receptor,neuropilin-1 (NP-1) in transgenic animals. In addition, sema3A and NP-1 expression will be interfered byusing viral vector mediated siRNA.KEY WORDS: Semaphorin 3A, degeneration, neuromuscular junction, amyotrophic lateral sclerosisTELEPHONE-NUMBER: 020-5665500E-MAIL-ADDRESS: t.vo@nih.knaw.nl26

TITLEGENETIC MODIFICATION OF HUMAN SURAL NERVE SEGMENTS BY A LENTIVIRAL VECTORENCODING NERVE GROWTH FACTORAUTHORSMartijn R Tannemaat MD 1,2 , Gerard J. Boer PhD 1 , Joost Verhaagen PhD 1 , Martijn J.A. Malessy MD PhD 2DEPARTMENT/INSTITUTE1 Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, Amsterdam; 2 Department ofNeurosurgery, Leiden University Medical Center, LeidenABSTRACTAutologous nerve grafts are used to bridge the gap between proximal and distal nerve stumps followingsevere peripheral nerve injury. Recovery of nerve function after grafting is rarely complete. Exogenousapplication of neurotrophic factors can enhance regeneration, but thus far the application of neurotrophicfactors has been hampered by poor penetration in nervous tissue, fast degradation following localapplication and unwanted side effects following systemic application. These problems may be overcomewith the use of lentiviral (LV) vectors which direct local, long-term transgene expression in cells. Therefore,we investigated the application of LV vectors to transduce cells in the most commonly used graft, the suralnerve, with the aim of increasing production of nerve growth factor (NGF) by the graft.Injection of vector into nerve segments is a faster and more effective way to deliver the vector thansubmersion of the nerve in vector containing medium. It generally leads to large numbers of transducedcells over a significant extent inside the nerve, the transduced cells being mainly fibroblasts outside thenerve fascicles. The injection of an LV vector encoding NGF leads to a gradual increase of NGF levels inthe medium when the sural nerve is placed in culture, reaching a plateau between 4 and 11 days. LV-NGFtransducedhuman fibroblasts promote neurite outgrowth in vitro. In an additional series of experiments weshow that the in vivo application of LV-NGF has promising functional and histological effects onregeneration in a rat model for peripheral nerve transection and repair.The gene therapeutic approach developed here holds promise as a powerful novel adjuvant therapy forperipheral nerve surgery and can be performed without changing the routine practice of nerve grafting.KEY WORDS: human nerve graft, lentiviral vector, transduction, nerve growth factor, peripheral nerveregenerationTELEPHONE-NUMBER: 020-5667130E-MAIL-ADDRESS: m.tannemaat@nin.knaw.nl27

TITLECOMPLEMENT INHIBITION FACILITATES REGENERATION OF THE INJURED PERIPHERAL NERVEAUTHORSValeria Ramaglia 1 , R.H.M. King 3 , M. Nourallah 3 , R. Walterman 1 , M.A. Vigar 4 , B.P. Morgan 4 andF. Baas 1,2DEPARTMENT/INSTITUTE1 Neurogenetics Laboratory and 2 Department of Neurology, Academic Medical Center, University ofAmsterdam, Amsterdam; 3 Department of Clinical Neurosciences, Royal Free and University CollegeMedical School, London, UK; 4 Department of Medical Biochemistry, University of Wales College ofMedicine, Cardiff, UK.ABSTRACTThe complement system is crucially involved in Wallerian degeneration (WD) of the peripheral nervoussystem (PNS). Its contribution in nerve regeneration remains, however, unknown. Here we show thatblockade of the complement cascade facilitates nerve regeneration and functional recovery following acutenerve trauma. We performed histopathological analysis of crushed sciatic nerves from wildtype and C6deficient rats, unable to assemble the cytolitic membrane attack complex (MAC). At 5wk post-injury, thewildtype animals showed clusters of thinly myelinated axons whereas the C6 deficient animals showedsingle myelinated axons and thick myelin sheaths, demonstrating faster axonal regeneration andremyelination. Recovery of motor and sensory function was also improved in complement deficient animals.Reconstitution of the C6 deficient animals with C6 restored the wildtype phenotype. In wildtype animals,inhibition of the complement cascade with soluble complement receptor 1 (sCR1) resulted in fasterrecovery of the sensory function compared to the PBS-treated animals. Pathological analysis of both, C6deficient and sCR1-treated nerves at 72h post-injury showed delayed Wallerian degeneration, inhibition ofmacrophage infiltration, no MAC deposition and delayed myelin clearance. We demonstrated that blockadeof the complement cascade improves regeneration of the injured peripheral nerve and we suggest that thisis achieved by preventing the damage caused by the MAC and/or activated macrophages during WD. Ourfindings open the door to a novel therapeutic approach in which blockade of the complement cascade couldpromote regeneration in peripheral neuropathies and neurodegenerative diseases where complementdependentnerve damage has been reported.KEY WORDS: Complement, crush injury, regeneration, recoveryTELEPHONE-NUMBER: 020-5664965E-MAIL-ADDRESS: v.ramaglia@amc.uva.nl28

TITLEGENERATION OF CONDITIONALLY IMMORTALIZED MOUSE SCHWANN CELLS FROM A PMP22OVEREXPRESSING MOUSE: UNRAVELING THE MOLECULAR MECHANISMS OF INHERITEDNEUROPATHIESAUTHORJose T. SaavedraDEPARTMENT/INSTITUTENeurogenetics Laboratory, Academic Medical Center, University of Amsterdam, AmsterdamABSTRACTAnimal models of inherited neuropathies have begun to show promise in the study of the molecularinteractions that lead to neuropathies. One such model is the C22 mouse which overexpresses 7 copies ofthe human PMP22 gene and has a severe demyelinating phenotype. PMP22 gene duplication is the causeof the majority of inherited demyelinating neuropathies also known as CMT1A. How the protein is directly(or indirectly) causing demyelination is not known. By studying the individual cellular components of theC22 mouse peripheral nervous system in culture we may be able to address the exact molecular cause ofdemyelinating neuropathies caused by PMP22 duplication. Progress has been slowed down significantly bythe difficulty inherent to the culture of mouse Scwhann cells (SCs). We have solved this problem bycrossing the C22 mouse with the transgenic “immortalized mouse” carrying a temperature sensitive SV40oncogene that is immortalizing at 33C and loses that function at higher temperatures. Upon activation of theSV40 promoter by IFN-γ, SCs cultured at the 33Cº permissive temperature are immortalized and replicateat a significantly higher rate than non-immortalized normal SCs. At the non-permissive temperature of 37Cºand in the absence of IFN-γ, replication returns to its normal rate and typical SC markers such as p75ngfrbecome expressed. We have also obtained 100% pure cultures by generating single cell clones viafluorescence activated cell sorting (FACS). With these cells we will confirm expression profile datapreviously generated in our lab from C22 mouse Schwann cells. Further confirmation will be done by RNAiknockdown of PMP22 overexpression to definitively link the gene expression profile to PMP22overexpression. This approach should yield a molecular blueprint of the effects of PMP22 on SCs inculture which will be followed up on with in vitro myelination.KEY WORDS: CMT1A, schwann cell, temperature sensitive SV40 oncogene, expression profilingTELEPHONE-NUMBER: 020-5663746E-MAIL-ADDRESS: j.t.saavedra@amc.uva.nl29

TITLEPARAMETRIC COCHLEAR IMPLANT FITTING ADJUSTMENTS BY RECIPIENTSAUTHORSKrista Willeboer, G.A. van Zanten, G.F. SmoorenburgDEPARTMENT/INSTITUTEAudiology – UMC Utrecht, UtrechtABSTRACTObjectiveImproving the cochlear implant (CI) speech processor fitting procedure, by giving recipients the possibilityto make manual adjustments during everyday life.MethodsCI recipients obtain a fitting in which the profile of the electrically evoked compound action potential (ECAP)threshold levels across the full electrode array, measured intra-operatively, is used. The overall level of theprofile is shifted by an equal amount of current units per electrode until we find the threshold for live speech(T profile) and the loudness comfort level for live speech (C levels) (Smoorenburg et al., 2002). This fittingis used for three weeks, after which speech perception with the conventional and ECAP-based fitting istested in quiet and noise. The next three weeks subjects are able to optimize sound quality by manuallyadjusting the overall level (shift) and inclination (tilt) of the profile of the C levels during daily use. Finally,speech perception is tested with the original and the adjusted ECAP-based fitting.ResultsSubjects primarily experiment with shift and tilt during the first two weeks of the three week period of selfadjustments.Averaged speech perception scores do not differ between the conventional and the adjustedECAP-based fitting. Some individuals however do show increased speech perception scores with theadjusted ECAP-based fitting.ConclusionThe CI recipient obtains the opportunity to optimize sound quality during everyday life. For this purpose, twoweeks is enough for the majority of recipients. Preliminary results do not show increased speechperception scores, however, in individual recipients significant increases are seen.References:Smoorenburg, G.F., Willeboer, C. and van Dijk, J.E. (2002). Speech perception in Nucleus CI24M cochlearimplant users with processor settings based on electrically evoked compound action potential thresholds.Audiol Neurootol, 7(6):335-47.KEY WORDS: Cochlear implant, electrically evoked compound action potential, speech processor fittings,speech perceptionTELEPHONE-NUMBER: 030–2507725EMAIL-ADDRESS: k.willeboer@umcutrecht.nl31

TITLEHOME SWEET HOME: CONTRIBUTION OF AUTOMATED HOME CAGE OBSERVATIONS TOBEHAVIOURAL GENETICSAUTHORLeonie de VisserDEPARTMENT/INSTITUTEAnimals, Science and Society, Utrecht University, UtrechtABSTRACTIn search for genes underlying complex CNS processes, behavioural phenotyping of inbred and geneticallymodified mice deserves full attention. Maybe trivial, but it is also one of the most challenging tasks inbehavioural genetics as behaviour is highly dynamic and complex and at the same time unpredictable andsensitive to confounding environmental factors that are either unaccounted for or practically unavoidable.Current behavioural assays have the advantage of an extensive literature backup and pharmacologicalvalidation, but are limited in the ability to study long-term effects on behaviour, circadian rhythms andaddress multiple interacting motivational systems in a single test setup. Moreover, factors like handling andtransport have considerable, but not well quantified impact on experimental outcomes in short-lasting tests.To tackle these problems, we developed a system that allows continuous registration of mouse locomotorbehaviour in a home cage environment (PhenoTyper ® , Noldus Information Technology, Wageningen, TheNetherlands). Testing animals in their home cage environment yields several advantages; it allowsobservations of habituation to the new home cage over consecutive days and the evaluation of bothchallenge-induced and baseline behaviours. Home cage testing also minimizes human intervention. Apartfrom detailed analysis of baseline activity and circadian rhythmicity, this set-up could be used to studyapproach-avoidance behaviour.We deliberately choose the approach of first thoroughly define and describe the various elements of homecage behaviour, how they interrelate and how they can be manipulated. Challenging the animals byexposing them to different stimuli and problems allows us to study approach-avoidance and learningbehaviour within the home cage environment. One of the major challenges resides in the pharmacologicalvalidation of the new home cage paradigms. First attempts in this direction have been undertaken todetermine the anxiogenic influence of an aversive light stimulus. Administration of an anxiolytic compound(diazepam) indeed decreased the observed avoidance behaviour when mice were exposed to the lightstimulus.Improving our understanding of the longitudinal aspects and dynamics of behaviour displayed in thestimulus-rich home cage environment will contribute to the ultimate goal of behavioural genetics: afunctional interpretation of the gene effect on behaviour.KEY WORDS: Behavioural phenotyping, ethology, anxiety, locomotor activityTELEPHONE-NUMBER: 06-45112581E-MAIL-ADDRESS: l.devisser@vet.uu.nl32

TITLEDISSECTING ANXIETY AND IMPULSIVITY AT A BEHAVIORAL AND GENOMIC LEVELAUTHORSMaarten Loos, I.J. van Zutphen, Z. Bochdanovits*, A.B. Smit, S. SpijkerDEPARTMENT/INSTITUTEDept. of Molecular and Cellular Neurobiology, *Dept. Medical Genomics, Center for Neurogenomics andCognitive Research, Vrije Universiteit Amsterdam, AmsterdamABSTRACTThe genetical and behavioral differences of common inbred mouse strains make them a valuable resourceto study the genetic contribution to complex behaviors, such as anxiety and impulsivity. In order todetermine the molecular encoding of these traits, we used a so-called behavioral-genomics approach. First,we measured the behavior of six common inbred mouse strains (129S6/SvEvTac, A/J, C3H/HeJ,C57BL6/J, DBA/2J and FVB/NJ) in a test battery of anxiety tests and the 5-choice serial reaction time task.Then, using discriminant analyses, we were able to extract 5 readily interpretable dimensions underlyingthe major components of behavior in our test battery. Subsequently, we retrieved gene expression datafrom 7 brain regions of these strains, and selected genes with a polymorphic profile across the 6 strains. Asubset of genes showed a polymorphic profile in more than one brain region, suggesting a strong geneticencoding. For these transcripts, we could identify enrichment in the number of highly significant cis-actingQTLs using an online gene expression data resource (webQTL). Finally, we correlated the expression ofselected genes to the 5 dimensions of the test battery across 6 strains. In addition to transcripts that havepreviously been associated with anxiety-related behavior, we identified transcripts that specifically correlatewith one of the 5 dimensions in our test battery. This analysis might provide a useful approach to thegenetic encoding of other complex traits.KEY WORDS: Neuropsychiatric disorders, genetical-genomics, gene expression, behavioral phenotypingTELEPHONE-NUMBER: 020 5989281E-MAIL-ADDRESS: maarten.loos@falw.vu.nl33

TITLETHE EFFECT OF CORTICOSTERONE ON AMPA RECEPTOR SUBUNIT LOCALISATION AND ITSEFFECT ON HIPPOCAMPAL SYNAPTIC EFFICIENCYAUTHORSOlof Wiegert A, , D. Holman B , M. Joëls A , C.C. Hoogenraad C , J.M. Henley B and H.J. Krugers A,DEPARTMENT/INSTITUTEACentre for Neuroscience, Swammerdam Institute for Life Sciences, Universiteit van Amsterdam,Amsterdam; B) Dept Anat, Univ Bristol Med Sch, Bristol BS8 1TT, United Kingdom C) Department ofNeuroscience, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, RotterdamABSTRACTBackgroundStressful and traumatic events are generally remembered well, but can also hamper the acquisition of novelinformation and retrieval of stored information. These effects are mediated, at least in part, by the adrenalhormone corticosterone (cortisol in humans). We have recently demonstrated that stress, and morespecifically the stress hormone corticosterone, regulates NMDA dependent LTP. It rapidly facilitates LTPwhile it reduces the ability to induce LTP over time, suggesting a genomic effect.The glutamatergic AMPA- and NMDA receptors play a crucial role in synaptic communication and inregulating synaptic plasticity. After NMDA receptor activation, calcium enters the cell in high amountsleading to synaptic incorporation of AMPA receptors. The incorporation of AMPA receptors leads to anenhanced synaptic transmission. Both the AMPA- and the NMDA receptors consist of different subunits. Inthe adult hippocampus two major subtypes of AMPA receptors exist, these contain either GluR1 andGluR2, or GluR2 and GluR3 subunits. The composition of the receptor is of relevance to their kinetics,which in its turn is essential for regulating synaptic plasticity. Subsequently, changes in localisation and/orcomposition of the glutamatergic receptors lead to a change in ability to alter synaptic plasticity. Thedynamic redistribution of glutamatergic receptors has come forward as a major mechanism for certain formsof changes in synaptic efficiency.AimIn this study we investigate whether the change in synaptic efficiency by corticosterone is due to analteration in the localization or composition of AMPA receptor subunits.KEY WORDS: AMPA, LTP, corticosterone , traffickingTELEPHONE-NUMBER: 020-5257661E-MAIL-ADDRESS: owiegert@science.uva.nl34

TITLEGABA A RECEPTOR FUNCTIONING IN HIPPOCAMPAL FAST NETWORK OSCILLATIONSAUTHORSTim Heistek, Huibert Mansvelder, Arjen BrussaardDEPARTMENT/INSTITUTEDepartment of Experimental Neurophysiology, Center for Neurogenomics and Cognitive Research (CNCR),Vrije Universiteit AmsterdamABSTRACTFast network oscillations occur in the hippocampus in the awake state and have been associated withmemory processing. These oscillations are generated in the pyramidal layer of the hippocampus and aredependent on perisomatic GABAergic inhibition from interneurons. Since GABA A receptor subunitcomposition determines the kinetics of GABAergic synaptic inhibition, we hypothesize that the frequency offast network oscillations is determined by the GABA A receptor subunits that are activated duringoscillations. Therefore, we try to clarify which GABA A receptor subtypes and interneuron types are involvedin fast network oscillations. Oscillations in acute brain slices from hippocampus can be induced with themuscarinic acetylcholine receptor agonist carbachol. Using a grid of 64 electrodes we examined thespatiotemporal patterns of fast network oscillations in the entire area of the hippocampus.Prolonging decay kinetics of GABAergic synaptic inhibition with benzodiazepines decreased the frequencyof carbachol-induced oscillations, indicating that GABA A receptor kinetics is involved in setting thefrequency at which the hippocampal network can oscillate. The α1-subunit specific benzodiazepinezolpidem also decreased the frequency of oscillations, indicating an involvement of α1-containing GABA Areceptors. These results suggest that the perisomatic inhibitory synapses between interneurons andpyramidal neurons in CA3, which have been shown to drive fast network oscillations, have α1-containingGABA A receptors. We are investigating whether the α1-containing GABA A receptors are the only importantreceptors in determining the frequency of oscillations. By making paired recordings between different typesof interneurons and pyramidal cells in oscillating slices we want to find out which connections are altered bybenzodiazepines, and which interneurons set the pace of firing in pyramidal cells.KEY WORDS: oscillations, network activityTELEPHONE-NUMBER: 020-5987032E-MAIL-ADDRESS: theistek@falw.vu.nl35

TITLEBLOOD-BRAIN BARRIER LEAKAGE MAY LEAD TO PROGRESSION OF TEMPORAL LOBEEPILEPSYAUTHORSErwin A van Vliet 1,2 , S. da Costa Araújo 2 , S. Redeker 3 , R. van Schaik 2 , E. Aronica 3 and J.A. Gorter 1,2DEPARTMENT/INSTITUTE1 Epilepsy Institute of The Netherlands (SEIN), Heemstede; 2 Swammerdam Institute for Life Sciences,Center for Neuroscience, University of Amsterdam, Amsterdam; 3 Academic Medical Center, Department of(Neuro) Pathology, University of Amsterdam, AmsterdamABSTRACTLeakage of the blood-brain barrier (BBB) is associated with various neurological disorders, includingtemporal lobe epilepsy (TLE). However, it is not known whether alterations of the BBB occur duringepileptogenesis and whether this can affect progression of epilepsy. We used both human and rat epilepticbrain tissue and determined BBB permeability using various tracers and albumin immunocytochemistry. Inaddition, we studied the possible consequences of BBB opening in the rat for the subsequent progressionof TLE. Albumin extravasation in human was prominent after SE in astrocytes and neurons, and also inhippocampus of TLE patients. Similarly, albumin and tracers were found in microglia, astrocytes andneurons of the rat. The BBB was permeable in rat limbic brain regions shortly after status epilepticus (SE),but also in the latent and chronic epileptic phase. BBB permeability was positively correlated to seizurefrequency in chronic epileptic rats. Artificial opening of the BBB by mannitol in the chronic epileptic phaseinduced a persistent increase in the number of seizures in the majority of rats. These findings indicate thatBBB leakage occurs during epileptogenesis and the chronic epileptic phase and suggest that this cancontribute to the progression of epilepsy.KEY WORDS: Albumin, seizure, fluorescein, evans blue, status epilepticusTELEPHONE-NUMBER: 020-5257893E-MAIL ADDRESS: vliet@science.uva.nl36

TITLEBRAIN VOLUMES IN RELATIVES OF PATIENTS WITH SCHIZOPHRENIA: A META-ANALYSISAUTHORSHeleen B.M. Boos, MS; André Aleman, PhD; Wiepke Cahn, MD, PhD; Hilleke Hulshoff Pol, PhD; René S.Kahn, MD, PhDDEPARTMENT/INSTITUTERudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht (MsBoos, Drs Hulshof, Cahn and Kahn); BCN NeuroImaging Center, University Medical Center Groningen (DrAleman)ABSTRACTObjectiveSchizophrenia is a disorder characterized by brain volume reductions particularly in the medial temporallobe. The extent to which brain abnormalities are related to a vulnerability to schizophrenia can beaddressed by examining first-degree relatives. This is the first meta-analysis which integrates all MRIstudies, examining global brain volumes and medial temporal lobe volumes, in first-degree relatives ofpatients with schizophrenia as compared to patients and healthy subjects.MethodA systematic search in the MEDLINE database was conducted to identify MRI studies in relatives ofpatients with schizophrenia as compared to healthy subjects. Studies had to report sufficient data forcomputation of the effect size. For each study Cohen’s d, was calculated. All analyses were carried out inthe random effects model.ResultsTwenty-three studies were identified as suitable for analyses. The analyses included 1,065 independentfirst-degree relatives of patients, 679 patients with schizophrenia, and 1,100 comparison subjects.Comparing relatives of patients with schizophrenia to healthy subjects hippocampal volume (d=0.31, 95%CI=0.13-0.49) and gray matter volume (d=0.18, 95% CI=0.01-0.35) were found reduced in relatives. Thirdventricle volume was increased (d=0.21, 95% CI=0.03-0.40). The hippocampal volume showed a furtherreduction in patients as compared to their relatives (d=0.46, 95% CI=0.19-0.72).Conclusions: This meta-analysis found that brain volume reductions are present in first degree relatives ofpatients with schizophrenia and that the hippocampus is most affected. Nevertheless, the volumereductions found in first-degree relatives are not as extensive as in patients.KEY WORDS: Meta-analysis, first-degree relatives, brain volumes, hippocampus, gray matter, ventriclesTELEPHONE NUMBER: 030-2509931E-MAIL-ADRESS: h.b.m.boos@umcutrecht.nl37

TITLEBRAIN VOLUME CHANGES IN MONOZYGOTIC AND DIZYGOTIC TWINS DISCORDANT FORSCHIZOPHRENIA: A 5-YEAR LONGITUDINAL MRI STUDYAUTHOR(S)Rachel G.H. Brans, Neeltje E.M. van Haren, G. Caroline M. van Baal, Hugo G. Schnack, René S. Kahn,Hilleke E. Hulshoff PolDEPARTMENT/INSTITUTERudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Centre Utrecht,A01.126, Heidelberglaan 100, 3584 CX UtrechtABSTRACTSibling and twin studies have revealed that genetic factors play an important role in the risk to developschizophrenia, and are related to the brain abnormalities found in these patients (Boos, in press). At least apart of the morphological brain changes in schizophrenia are progressive over the course of the illness.Whether these progressive brain changes in schizophrenia are mediated by genetic or disease-relatedfactors is inconclusive. A study in probands and their healthy siblings suggested that disease related(possibly non-genetic) factors may be involved in the progressive changes in total brain volume (TBV) andgray matter volume in schizophrenia (Brans, submitted). However, this setup may have underestimatedgenetic influences. To draw more final conclusions, two 1.5 T MRI brain scans were obtained frommonozygotic (MZ) and dizygotic (DZ) twins discordant for schizophrenia (23 MZ and 23 DZ subjects) andmatched healthy comparison twin pairs (29 MZ and 27 DZ subjects) with a scan interval of 5 years.Compared to the baseline sample (Hulshoff Pol, 2004) 91% participated at follow-up.Quantitative assessments of intracranial, total brain, gray and white matter of the cerebrum, lateral and thirdventricles volumes were performed. Disease and familial related effects for progressive TBV changes inschizophrenia were analyzed using structural equation modeling with Mx software. Multivariate geneticmodel fitting was applied to schizophrenia liability and brain volumes, correcting for age at baseline, genderand intracranial volume.A high heritability for the stable trait of TBV was found (within subject test-retest corr. = 0.86; MZ corr. =0.81; DZ corr. = 0.27). Schizophrenia liability was associated with a smaller TBV (within-subject cross-traitcorr. = -0.26; cross-trait/cross-twin MZ corr. = -0.21; DZ corr. = -0.11). Over time, a decrease of TBV wasfound, which was moderately correlated within twin pairs irrespective of disease (MZ corr. = 0.43 and DZcorr. = 0.34). The decrease in TBV became more pronounced with higher schizophrenia liability due togenetic or common environmental factors (cross–member cross–trait MZ corr. = -0.18 and DZ corr. = -0.18). Other brain volumes are currently being analyzed. These preliminary findings suggest that theprogressive total brain volume changes in schizophrenia may be mediated (in part) by genes.This research was supported by Grant No. 908-02-123 (HEH) from the Netherlands Organization for HealthResearch and Development ZonMw.References:Boos et al. Brain volumes in relatives of patients with schizophrenia: a meta-analysis. In press.Brans et al. Structural brain changes in patients with schizophrenia and their healthy siblings: a 5-yearfollow-up MRI study. Submitted.Hulshoff Pol et al. Gray and white matter volume abnormalities in monozygotic and same-gender dizygotictwins discordant for schizophrenia. Biol.Psych., 55, 126-130.KEY WORDS: Structural imaging, schizophrenia, twin studyTELEPHONE NUMBER: 030-2508352E-MAIL-ADDRESS: r.brans@azu.nl38

TITLEGENETICS OF SCHIZOPHRENIA: SEGREGATION ANALYSIS OF ENDOPHENOTYPESAUTHORSMaartje F. Aukes 1 , B.Z. Alizadeh 2, M.M. Sitskoorn 1, J.P. Selten 1 , R.J. Sinke 2 , R.S. Kahn 1DEPARTMENT/INSTITUTE1 Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht,Utrecht; 2 Department of Biomedical Genetics, University Medical Center Utrecht, UtrechtABSTRACTBackgroundEndophenotyping is a promising strategy for genetic research on complex psychiatric disorders asendophenotypes improve power of a study while they may reduce genetic architecture. In the presentstudy, we investigated heritability and genetic transmission patterns of several endophenotypes includingverbal memory, set shifting and fine motor functioning in Dutch families with schizophrenia.MethodsThirty high-risk families including 138 subjects (15 probands and 123 of their relatives) were administeredthe CVLT delayed recall task, the Trailmaking task and the Purdue pegboard task. A segregation analysiswas performed on the age and sex adjusted levels using the SEGREG module of S.A.G.E.ResultsWe found significant evidence of oligogenic inheritance of the three studied endophenotypes. We found noevidence for a Mendelian mode of transmission. The segregation analysis showed a homogeneous generalmodel of transmission best fitted the verbal memory data and a heterogeneous general model best fittedthe fine motor functioning data. When compared with a model with no genetic effect, the Akaike’sInformation Criteria (AIC’s) were significantly lower for verbal memory (525.28 versus 531.72; p=.04) andfine motor functioning (698.88 versus 700.50; p=.05). For set shifting the environmental model could not berejected.ConclusionsOur findings suggest an underlying genetic transmission for verbal memory and fine motor functioning. Theparameters estimated can augment further genetic study relevant to identify genetic factors involved inthese traits in these families. Data will be presented linking the endophenotype data to the liability forschizophrenia.KEY WORDS: Endophenotypes, schizophrenia, heritabilityTELEPHONE-NUMBER: 030-2501783E-MAIL-ADDRESS: m.aukes@umcutrecht.nl39

TITLETHE COMT val 158 met POLYMORPHISM AND BRAIN MORPHOMETRY IN HEALTHY YOUNG ADULTSAUTHORSJanneke Zinkstok 1,2 , Nicole Schmitz 1 , Therese van Amelsvoort 1 , Maartje de Win 3 , Wim van den Brink 1, 4 ,Frank Baas 2 and Don Linszen 1DEPARTMENT/INSTITUTE1 Department of Psychiatry, Academic Medical Center-University of Amterdam (AMC-UvA), Amsterdam; 2Neurogenetics Laboratory, AMC-UvA, Amsterdam; 3 Department of Radiology, AMC-UvA; 4 AmsterdamInstitute of Addiction Research, AmsterdamABSTRACTBackgroundCatechol-O-Methyltransferase (COMT) is the most important mechanism for dopamine degradation in theprefrontal cortex and contains a functional polymorphism (val 158 met) influencing enzyme activity. The lowactivitymet allele has been associated with better performance on cognitive tasks relying on the prefrontalcortex. Whether COMT also affects brain structure, is still unclear. This study investigated the relationshipbetween the COMT val 158 met polymorphism and brain anatomy in healthy young adults.MethodsIn a cross-sectional study, structural MRI data and DNA for COMT genotyping were obtained from 154healthy young adults. Statistical Parametric Mapping software (SPM2) and optimized voxel-basedmorphometry were used to determine total and regional gray and white matter density differences betweengenotype groups, as well as age-related gray and white matter density differences within the genotypegroups.ResultsWe found a significant effect of COMT genotype on age-related differences in gray and white matter densityin females but not in males. In female val carriers increased gray matter in the temporal and parietal lobeand the cerebellum and increased white matter in the frontal lobes were positively correlated with age; infemale met homozygotes decreased gray matter density in the parietal lobe and decreased white matterdensity in the frontal lobes, the parahippocampal gyrus and the corpus callosum were positively correlatedwith age.ConclusionThese results suggest that the COMT val 158 met polymorphism may affect age-related differences inregional gray and white matter density in females.KEY WORDS: Catechol-O-methyltransferase, brain anatomy, voxel-based morphometry, age, genderTELEPHONE-NUMBER: 020-5662001/ 06-17456044E-MAIL-ADDRESS: j.r.zinkstok@amc.uva.nl40

TITLETHE ROLE OF THE AGGREGATION STATE OF AMYLOID-β ON ITS NEUROTOXICITYAUTHORSSidhartha M. Chafekar a , Hinke Malda b , Maarten Merkx b , Bert W. Meijer b , Hilal A. Lashuel c , Frank Baas aand Wiep Scheper aDEPARTMENT/INSTITUTEa Neurogenetics Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam; b Laboratoryof Macromolecular and Organic Chemistry, Eindhoven University of Technology, Eindhoven; c IntegrativeBiosciences Institute, Laboratory of Molecular Neurobiology and Neuroproteomics, Swiss Federal Instituteof Technology (EPFL), Lausanne, SwitzerlandABSTRACTOne of the neuropathological hallmarks of Alzheimer’s disease (AD) is accumulation and aggregation of themisfolded β-amyloid protein in extracellular plaques. Aggregation of Aβ occurs via several conformationalstates including dimers, spherical oligomers and protofibrils before finally reaching their insoluble fibrillarconformation. The exact nature of the Aβ species causing toxicity and eventually neurodegeneration in vivois not known, but increasing evidence indicates that Aβ must be in an aggregated state for it to be toxic:This suggests that prevention of Aβ aggregation may inhibit Aβ toxicity.The initial studies on the aggregation process of Aβ by (Hilbich et al., 1992) and (Tjernberg et al., 1996)identified the critical region of Aβ involved in amyloid fibril formation. The hydrophobic core at residues 16-20 of Aβ, KLVFF, is crucial for the formation of β-sheets by Aβ. Peptides incorporating this short Aβfragment (KLVFF, Aβ16-20) can not only bind full-length Aβ but also prevent its aggregation into amyloidfibrils. In this study we have made use of this fragment as well, by designing a molecule that containsmultiple copies of KLVFF. Therefore we used dendrimers, a chemical structure that served as a scaffold forthe attachment of 4 copies of the KLVFF-peptide. The aim of this study was to study the effect of thisdendrimeric KLVFF (K 4 ) on Aβ aggregation in vitro. These effects were compared to the effect ofmonomeric KLVFF (K 1 ) on Aβ aggregation. The main research question we would like to answer is if K 4 is amore potent inhibitor of Aβ aggregation then K 1 .In this study we show that K 4 inhibits Aβ aggregation very effectively, in a concentration dependent mannerand in a much more potent way then K 1 . In addition, we show that K 4 can even break down protofibrillaraggregates. These data show that multiple copies of KLVFF on one molecule has an increased inhibitoryeffect on Aβ aggregation. Future studies will determine whether this peptide-dendrimer is a potential drugcandidate for preventing Aβ neurotoxicity.KEY WORDS: Alzheimer’s disease; ß-amyloid; aggregation inhibitor; dendrimersTELEPHONE-NUMBER: 020-5664959E-MAIL-ADDRESS: S.M.Chafekar@amc.uva.nl41

TITLEIDENTIFICATION OF TRANSCRIPTIONAL ALTERATIONS IN HUMAN POSTMORTEM BRAINS OFPARKINSON’S DISEASE AND ALZHEIMER’S DISEASEAUTHORSKoen Bossers 1,2 , G. Meerhoff 1 , C. Kruse 3 , J. Verhaagen 1 , D.F. Swaab 2DEPARTMENT/INSTITUTE1 Workgroup Neuroregeneration, 2 Workgroup Neuropsychiatric Diseases, Netherlands Institute forNeuroscience, Amsterdam, 3 Solvay Pharmaceuticals, Weesp, 4 Netherlands Brain Bank, AmsterdamABSTRACTParkinson’s Disease (PD) and Alzheimer’s Disease (AD) are both progressive neurodegenerativedisorders, affecting increasingly large numbers of people and pose a huge socio-economical burden tosociety. During the past decades, mutations in several genes have been identified that cause genetic formsof PD and AD. These findings have greatly increased our understanding of the molecular mechanismsunderlying these diseases. However, the majority of PD and AD cases are of sporadic origin. It is still veryunclear whether the mutated genes in familial PD and AD are major players in sporadic forms of thediseases. Therefore, studies looking beyond the genes that are already implicated in PD and AD arewarranted.We have performed microarray studies on human postmortem brain material from PD and AD, andsuccessfully identified transcriptional differences between diseased and healthy individuals. Advancedbioinformatics approaches were also employed to pinpoint changes in the biological processes andpathways.For PD, we analyzed the caudate nucleus, putamen and substantia nigra of PD patients and controls.Subtle changes in the caudate nucleus and putamen, and robust expression changes in the substantianigra were observed. Using functional class scoring, we identified dysregulation of several processesimportant to neuronal survival, amongst others the mitochondrial system, the ubiquitin-proteasome systemand microtubular integrity and transport.The progression of AD can be monitored by the stepwise occurrence of neurofibrillary tangles in particularareas of the brain as classified in 7 Braak stages, where Braak 0-2 represent non-demented controls, Braak3-4 mild cognitive impairment, and Braak 5-6 full-blown AD. We performed microarray experiments tomonitor gene expression changes associated with each Braak stage. Transcriptional profiles weregenerated from the frontal medial gyrus of 49 individuals, 7 for each Braak stage. Several unique clusters oftranscripts were successfully identified that change throughout the progression of AD. Some of theseclusters already show alterations well before the clinical manifestation of AD, and might be the first sign ofthis devastating neurodegenerative disorder.KEY WORDS: Gene expression, Parkinson’s Disease, Alzheimer’s Disease, time course, post mortemTELEPHONE-NUMBER: 020-5665512E-MAIL-ADDRESS: k.bossers@nin.knaw.nl42

TITLEIMAGING PREFRONTAL CONSEQUENCES OF CHRONIC INSOMNIA: RESULTS OF TWO VERBALFLUENCY TASKS AND A SET SHIFTING TASK IN fMRIAUTHORSEllemarije Altena*#, Ysbrand D. van der Werf*#, Ernesto J. Sanz-Arigita*, Rebecca G. Schutte*, Eus J.W.van Someren*#DEPARTMENT/INSTITUTE* Netherlands Institute for Neuroscience, KNAW, Amsterdam; # VU Medical CentreABSTRACTPrefrontal functions such as planning, set shifting and verbal fluency are known to be affected by sleepdeprivation in healthy young subjects. The effects on prefrontal functioning in ‘natural’ long term sleepdeprivation such as occurs in patients suffering from psychophysiological insomnia however, are so far notwell known. We combined neuropsychological assessments, fMRI and EEG to investigate the prefrontalconsequences of chronic insomnia in healthy elderly, an age-group most affected by this condition.Here, I will present behavioral and functional imaging data of two verbal fluency tasks and a set shiftingtask of 21 patients suffering from psychophysiological insomnia and 12 healthy, age matched controlsubjects. Since patients with chronic insomnia have relatively few cognitive impairments despite alongstanding sleep disorder, we hypothesized that compensatory mechanisms may occur in performingthese tasks, similar to compensatory processes in early stages of Parkinson’s disease and Alzheimer’sdisease. We will show behavioral and imaging data corresponding to this hypothesis.KEY WORDS: Sleep, cognition, imagingTELEPHONE-NUMBER: 020-4440685E-MAIL-ADDRESS: e.altena@vumc.nl43

TITLEOBESE RATS BY LENTIVIRAL-MEDIATED TRANSGENESISAUTHORSMarijke de Backer, Maike Brans, Keith Garner, Mariken de Krom, and Roger A.H. AdanDEPARTMENT/INSTITUTEPharmacology and Anatomy, RMI, UtrechtABSTRACTWe generate transgenic rats using a novel transgenesis technique in combination with siRNA sequences inorder to validate drug target genes in advanced animal models with a focus on genes involved inpsychiatric disorders and genes involved in central regulation of energy metabolism.Recently we succeeded to generate transgenic mice using this novel technique (injection of lentiviralparticles carrying siRNA sequences against the MC4-receptor into the perivitelline space of one-cell stageembryos; Lois et al 2002 and Rubinson et al 2003) with a high success rate (40 % transgenesis). We alsosucceeded in generating transgenic rats using the same technology. Knockdown of the MC4 receptorresulted in an obese phenotype.KEY WORDS: Lentiviral vector, transgenesis, obesity, MC4-RTELEPHONE-NUMBER: 030-2533634E-MAIL-ADDRESS: m.debacker@med.uu.nl44

TITLERECENT DEVELOPMENT IN THE MOLECULAR PATHOGENESIS OF HEMIMEGALENCEPHALY INPATIENTS WITH INTRACTABLE EPILEPSYAUTHORSKarin Boer 1 , D. Troost 1 , W.G.M. Spliet 2 , S. Redeker 1 , P.C. van Rijen 3 , P.B. Crino 4 andE. Aronica 1DEPARTMENT/INSTITUTE1 Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam;2 Department of Pathology, UMCU, Utrecht; 3 Department of Neurosurgery/Rudolf Magnus Institute forNeurosciences, UMCU, Utrecht; 4 PENN Epilepsy Center, Department of Neurology, University ofPennsylvania Medical Center, Philadelphia, USAABSTRACTHemimegalencephaly (HMEG) is a malformation of cortical development characterized by unilateralenlargement of one cerebral hemisphere, severe architectural and cellular abnormalities and an associationwith intractable epilepsy. The molecular pathogenesis of HMEG remains largely unknown, howeverprevious evidence demonstrated enhanced activation of the Wnt-1/β-catenin pathway in HMEG. Weinvestigated immunohistochemically the expression of a downstream protein of the Wnt-1/β-cateninpathway, Cyclin D1, as well as activation of the mTOR pathway in autopsy and surgical HMEG cases.Expression of cyclin D1 was detected in the nuclei of dysmorphic neurons and balloon cells in all 8 HMEGspecimens tested. A downstream effector of the mTOR pathway, phospho-S6 ribosomal protein (pS6), wasalso observed in dysmorphic neurons and balloon cells. Double immunolabeling experiments demonstratedthat cyclin D1 labeled cells were concomitantly labeled with the pS6 antibody. Double immunolabeling withGFAP revealed that astrocytes did not express cyclin D1 or pS6. The expression of cyclin D1 and pS6 wasundetectable in the unaffected contralateral hemisphere and normal control cortex.In conclusion, our findings indicate cell specific activation of both the Wnt-1/β-catenin pathway and themTOR pathway, which might contribute to cytomegaly and hemispheric enlargement in this brainmalformation.KEY WORDS: Hemimegalencephaly, molecular pathogenesis, immunohistochemistry, intractable epilepsyTELEPHONE-NUMBER: 020-5664369E-MAIL-ADDRESS: karin.boer@amc.uva.nl45

TITLENEURAL CODING OF ATTENTIONAL PROCESSES IN MOUSE PREFRONTAL CORTEXAUTHORSMarieke de Boer, M. van der Roest, S. Ozcelik, A. Bouhbouh, A. B. MulderDEPARTMENT/INSTITUTECNCR-Cognitive Neurophysiology, Dept. of Anatomy and Neurosciences, VU University medical center,AmsterdamABSTRACTPrimate (including human) prefrontal cortex is concerned with many complex cognitive functions which areoften described as ‘executive’. For example, dorsolateral prefrontal cortex is thought to be involved inworking memory, decision-making, reasoning, temporal organization of behaviour, and attentional control.Likewise, the rodent medial prefrontal cortex (mPFC) is critically involved in the guidance of behaviour. Itgoverns functions like spatial working memory and movement planning. Furthermore, the mPFC has beenimplicated in attentional functions such as detection of stimulus features, attentional set-shifting andbehavioural flexibility. Very little electrophysiological data exist to back up behavioural, anatomical, andpharmacological evidence on the involvement of the mPFC in attention. Therefore, we set out to investigatethe underlying neuronal mechanisms by recording neuronal activity in the prefrontal circuit, with specialemphasis on the mPFC, in freely behaving mice. Adult male C57BL/6 mice (> 28 grams) are trained toperform a modified five-choice test of attention. In various stages of the task we recorded mPFC unitactivity and local EEG, focussing on prelimbic and infralimbic areas, using a multiple tetrode driver(Neuralynx: 16 channels) linked to a Plexon data acquisition system. So far, two mice were recorded. Unitswere sorted using Offline Sorter (Plexon) and further analysed using NeuroExplorer. These units revealedevent-related activity, such as inhibition of firing after reward delivery. In addition, location-dependent firingwas found. Elucidating neurophysiological substrates within the attentional circuitry, including BasalForebrain, Dorsal Raphe, Locus Coeruleus, and Ventral Tegmental Area, might be of clinical relevance forinattentiveness in psychiatric conditions such as ADHD.KEY WORDS: Attention, prefrontal circuit, mPFC, in-vivo recordings, modified five-choice taskTELEPHONE-NUMBER: 020-4448047E-MAIL-ADDRESS: marieke.deboer@vumc.nl46

TITLEOLFACTORY TESTING IN DUTCH PARKINSON’S DISEASE PATIENTSAUTHORSSanne Boesveldt 1 , D. Verbaan 2 , J.J. van Hilten 2 , H.W. Berendse 1DEPARTMENT/INSTITUTE1 Department of Neurology, VU University Medical Center, Amsterdam; 2 Department of Neurology, LUMC,LeidenABSTRACTIntroductionRecent studies have shown that hyposmia may be a prodromal sign of neurodegenerative disorders, mostnotably Parkinson’s disease (PD) and Alzheimer’s disease. The “Sniffin’Sticks” is a quantitative test batteryof olfactory function. Normative values for this test are available for German individuals only, which limits itsuse in the Dutch population.The present study was initiated to establish normative values for two of the components (odouridentification and odour discrimination) of the “Sniffin’Sticks” in the Dutch elderly population. Subsequently,these values were used to determine the prevalence and degree of olfactory dysfunction in a largepopulation of Dutch patients suffering from Parkinson’s disease.MethodsOlfactory function was assessed in 118 healthy controls, (45 women, mean age 59.4 years, range 45-78years) using the odour identification and discrimination parts of the “Sniffin’ Sticks” test battery. Odouridentification was measured by presenting 16 odorants in suprathreshold intensity in a multiple (4)-forcedchoice format. In the odour discrimination test, subjects were asked to select the odd odour out of threeodorants presented, without the need to recognize or name the odours. In both tests, olfactory scores weredefined as the number of correct answers (0-16). For the second part of the study, the same olfactory testswere used in 385 PD patients (143 women, mean age 61.7 years, range 40-90 years, H&Y stages I-V).ResultsPreliminary data suggests that the mean identification score for healthy subjects was 12.9 (sd 2.1); therewas no age effect. The mean discrimination score was 11.5 (sd 2.3), with a significant decline in scoreswith increasing age.PD patients scored significantly worse on both olfactory tests an average score of 7.4 (sd 3.0) on theidentification test and a score of 8.0 (sd 2.6) on the discrimination task. PD women outperformed men onboth tasks. Furthermore, olfactory function in PD patients decreased with age.ConclusionNormative values have been established for the Dutch population for the identification and discriminationpart of the “Sniffin’Sticks”. PD patients performed worse than healthy controls on both tests. Definitiveresults will be presented at the annual meeting.KEY WORDS: Olfaction, Parkinson’s disease, clinicalTELEPHONE NUMBER: 020 4440708E-MAIL-ADDRESS: s.boesveldt@vumc.nl47

TITLEDOES BRAIN VOLUME CHANGE AFTER WITHDRAWAL OF ANTIPSYCHOTIC MEDICATION INFIRST-EPISODE SCHIZOPHRENIA?AUTHORSGeartsje Boonstra, MD, H.E. Hulshoff Pol, PhD, N.E. van Haren, PhD, H.G. Schnack, PhD, H. Burger, PhD,D.E. Grobbee, PhD, R.S. Kahn, PhDDEPARTMENT/INSTITUTEDepartment of Psychiatry, UMCU, UtrechtABSTRACTAlthough influence of antipsychotic medication on brain morphology has been demonstrated manyquestions remain unanswered. Ideally, the impact of antipsychotic treatment should be assessed withstudies performing sequential MRI scans in patients on and off antipsychotic medication. We conducted alongitudinal structural MRI study in which changes in brain volume were compared between schizophreniapatients who discontinued and those that continued antipsychotic medication.Of 30 remitted, stable first-episode schizophrenia patients 20 were randomized to continuation ordiscontinuation of antipsychotic medication while 10 patients continued or discontinued medication withouthaving been randomized. All were included in a 2-year follow-up. On a 1.5T scanner 112 brain scans, 3-5scans per patient, (25 medication-free scans and 89 on medication), were made in 26 patients at baselineand at 6, 12 and 24 months of follow-up as well as after a relapse occurred. Thirty-six healthy controls werealso scanned twice with a 1-year interval.Preliminary analyses were performed in a selection of scans, with patients divided in three subgroups: Adiscontinuation group (antipsychotic treatment discontinued at the second scan, n=12, ≤ 6 months scaninterval),a continuation group (patients continued medication, n=14, 6 months scan-interval) and an agematchedhealthy control group (n=15, 1-year scan-interval). A one-way between-groups analysis ofvariance was conducted to explore the impact of medication discontinuation on total brain, third and lateralventricle, cerebellar, cerebral gray matter (GM) and white matter volume changes, after correction forintracranial volume and age.A statistically significant difference in cerebral gray matter (GM) volume change for the three subgroups[F(2, 38)=4.7, p=.015] was found (Eta squared effect-size=0.2). Post-hoc pair-wise comparisons indicatedthat the GM volume change in the discontinuation group (Mean (M)=-14.7ml, SD=16.2) was significantlydifferent from the change in the control group (M=8.8ml, SD=21.2). The continuation group (M=-.9ml,SD=24.3) did not differ from the controls or the discontinuation group.This study suggests that continued use of atypical antipsychotics is associated with less decrement ofcerebral GM volume in schizophrenia patients. A time-series analyses is planned including all scans, toenhance the robustness of the analyses.KEY WORDS: Neuro-imaging, first-episode, schizophrenia, discontinuation, antipsychotic treatmentTELEPHONE-NUMBER: 030-2507121E-MAIL-ADDRESS: g.boonstra@umcutrecht.nl48

TITLELONG-TERM BEHAVIORAL CHANGES AFTER CESSATION OF CHRONIC ANTIDEPRESSANTTREATMENT IN OLFACTORY BULBECTOMIZED RATSAUTHORSMegan E. Breuer, Lucianne Groenink, Ronald S. Oosting, Herman G.M. Westenberg, Berend OlivierDEPARTMENT/INSTITUTEDepartment of Psychopharmacology, Utrecht Institute for Pharmaceutical Sciences, Universiteit Utrechtand Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center, UtrechtABSTRACTBackgroundOlfactory bulbectomy (OBX) in rats causes several behavioral and neurochemical CNS changes,reminiscent of symptoms of human depression. Moreover, depression-like behavior after OBX can bereversed with antidepressants. However, the lasting effects of these antidepressants on behavior aftercessation of treatment have never been studied.MethodsMale rats received olfactory bulbectomy or sham surgery. After recovery, animals received fourteenconsecutive daily doses of imipramine (20 mg/kg), escitalopram (5 and 10 mg/kg), or vehicle. Animals weretested in an open field after acute, sub-chronic and chronic injections, as well as 1, 2, 6 and 10 weeks aftercessation of treatment.ResultsOBX induced hyperactivity was normalized after (sub) chronic administration of imipramine andescitalopram. Two weeks post-treatment, activity of OBX animals was comparable to shams, but after sixweeks, OBX animals treated with both doses of escitalopram had returned to pre-treatment hyperactivitylevels. OBX animals treated with the high imipramine dose (20 mg/kg) retained activity levels comparable toshams until 10 weeks after cessation of treatment.ConclusionsChronic, but not acute, administration of imipramine and escitalopram normalizes OBX inducedhyperactivity. This effect continues for up to 10 weeks after cessation of treatment in a dose dependantmanner.KEY WORDS: Olfactory bulbectomy, open field, depression, imipramine, escitalopram, cessation oftreatmentTELEPHONE-NUMBER: 030-2537382E-MAIL-ADDRESS: m.e.breuer@pharm.uu.nl49

TITLETHE ROLE OF NEUROTRANSMITTER SECRETION DURING AXON OUTGROWTH ON GROWTHCONE DYNAMICSAUTHORSJurjen H.P. Broeke, M. Roelandse, M. VerhageDEPARTMENT/INSTITUTEFunctional Genomics (FGA), Center for Neurogenomics and Cognitive Research (CNCR), VrijeUniversiteit Amsterdam, AmsterdamABSTRACTDirected axonal outgrowth is important during brain development and secretion may play an important rolein this process. Using silent mutants (munc13-1/2 double knockout and munc18-1 null), we investigated therole of secretion on growth cone dynamics such as outgrowth speed, accumulated distance travelled, thenumber of filopodia and their length as well as the growth cone area and motility. Work in dissociatedcultures of controls and silent mutants has shown that outgrowth is decreased and motility is increased insilent neurons. When AMPA is added at 3DIV to wild type neurons, the outgrowth is increased, but not insilent neurons. In organotypic slice cultures of both silent mutants at 3DIV using time lapse imaging wefound that AMPA increased the speed of directed outgrowth in WT but not in silent mutants. The resultssuggest that secretion regulates directed outgrowth through a presynaptic autocrine feedback loop.KEY WORDS: Axonal outgrowth, growth cone motility, secretion, organotypic cultures, Munc13, Munc18TELEPHONE-NUMBER: 020-5986929E-MAIL-ADDRESS: jurjen@cncr.vu.nl50

TITLENEURON DIVERSITY IN THE MEDIAL ENTORHINAL CORTEX OF THE RATAUTHORSCathrin B. Canto 1,2 , P. Ganter 1 , E. I. Moser 1 , M. Moser 1 , *M. P. Witter 2,1DEPARTMENT/INSTITUTE1 Centre for the Biology of Memory, NTNU, Trondheim, Norway, 2 Dept Anatomy and Neuroscience, VUUniversity medical center, AmsterdamABSTRACTThe medial entorhinal cortex (MEC) comprises a number of layers, each harboring a variety of neurons thatare the elements of functional intrinsic and extrinsic networks. Neurons in the MEC of rats code informationabout position, directionality and velocity and may thus enable complex navigational behavior. All layerscontain grid cells and grids of neighboring cells across layers share a common orientation and spacing(Sargolini et al., 2006). The organization of the neuronal network in MEC which underlies the reportednavigational functionality is unknown. In the present study we aim to understand the organization of theneuronal network in MEC in relation to the reported interaction between functional cell types as describedby Sargolini and colleagues. Using an in vitro approach, we characterized over 130 neurons in all layers ofMEC electrophysiologically through whole-cell current-clamp recordings. Our study includes layer Ineurons, which so far have not been investigated physiologically. All neurons were filled with Biocytin/Alexa555 or Biocytin/Alexa 633 and subsequently reconstructed, including dendritic and axonal arbors. Our dataextend the current knowledge regarding the physiology and anatomy of cells within the MEC. For every cellwe determined firing properties, such as spike-frequency adaptation, properties of the actionpotentials,characteristics of the afterpotentials, rebound activity, inward rectification, membrane potential oscillationsand the resonance properties of the cell. In addition we analyzed the morphological characteristics of thecells, such as axonal projections and the detailed geometry of the dendrites, form of soma and location ofthe soma within the layer. These findings help us to understand the potential organizational principles ofmicrocircuits in the entorhinal cortex, which might underlie grid-cell firing in MEC.KEY WORDS: Entorhinal cortex, Anatomy, morphology, electrophysiologyTELEPHONE-NUMBER: 020-4448049E-MAIL-ADDRESS: cathrin.canto@gmail.com51

TITLEADOLESCENT NICOTINE EXPOSURE IMPAIRS PERFORMANCE IN A VISUOSPATIAL ATTENTIONTASK DURING ADULTHOODAUTHORSDaniëlle S. Counotte, T. Pattij, T.J. de Vries, A.N.M. Schoffelmeer, S. Spijker, A.B. SmitDEPARTMENT/INSTITUTEDepartment of Molecular and Cellular Neurobiology, Center for Neurogenomics & Cognitive Research, VrijeUniversiteit, Amsterdam. Department of Anatomy and Neurosciences, Center for Neurogenomics andCognitive Research/ VUmc, AmsterdamABSTRACTAdolescence is a critical period of brain development during which many people come into contact with“socially accepted” drugs, such as nicotine. Human epidemiological data have shown that adolescentnicotine use is associated with an increased risk for developing psychiatric and addictive disorders later inlife. However, in humans these effects of early drug exposure result from a complex interaction of geneticmake-up, drug exposure and environmental influences. These confounding factors prevent the analysis ofwhether adolescent drug exposure causally contributes to the possible development of cognitive disordersin adulthood. Therefore, in this project we use animal models to assess the direct long-term behavioral andmolecular effects of adolescent nicotine exposure.In the present study, male Wistar rats were pretreated for ten days with saline or nicotine (three times daily0.4 mg/kg s.c.) either during peri-adolescence (PN34-43) or post-adolescence (PN60-69)(n=12 per group).Five weeks later, when both groups were adult, they were trained in the 5-choice serial reaction time task, aparadigm that measures various aspects of visuospatial attention, as well as inhibitory response control.Results indicated that animals exposed to nicotine during adolescence show decrements in attentionalperformance compared to the saline-treated controls. In addition, we found impairments in inhibitoryresponse control in these animals, exemplified by increased premature responding, a measure forimpulsive behavior. In contrast, animals pretreated with nicotine during post-adolescence were not differentfrom their saline-treated controls with respect to attentional function and inhibitory response control. Thiseffect persisted in the peri-adolescent groups when the attentional load was increased (=shorter stimulusduration or longer inter-trial interval, whereas the post-adolescent treated groups did not show differences.Finally, pharmacological challenges with nicotine (dose range: 0.04 – 0.4 mg/kg, s.c.) indicated that nicotinedecreased accuracy in all groups, but to a larger extent in animals pretreated with nicotine duringadolescence. Acute nicotine treatment also decreased response latency and increased prematureresponses in all groups similarly.Taken together, our data show that nicotine administration during adolescence has long-termconsequences for cognitive performance in adulthood. Currently, we are investigating the underlyingmolecular mechanisms triggered by adolescent nicotine exposure that might lead to these behavioraleffects in adulthood.KEY WORDS: Adolescence, nicotine, attention, cognitionTELEPHONE-NUMBER: 020-5987122E-MAIL-ADDRESS: danielle.counotte@falw.vu.nl52

TITLECESSATION OF CANNABIS USE IN PATIENTS WITH RECENT-ONSET SCHIZOPHRENIAAUTHORSNienke Dekker, L. de Haan, S.v.d. Berg, M. de Gier, H. Becker, D.H. LinszenDEPARTMENT/INSTITUTEPsychiatry AMC-UvA, Adolescentenkliniek, AmsterdamABSTRACTPatients with first-episode schizophrenia have a high rate of comorbid substance use disorder, withcannabis being a prominent drug of abuse. For the prevention and treatment of cannabis use amongschizophrenia patients, not only knowledge of factors which influence the initiation and continuation ofcannabis use is crucial, but also the factors associated with cessation of cannabis use are important.As opposed to the numerous studies that have been conducted investigating self-reported reasons forcannabis use in patients with psychotic disorders, little is known about self-reported reasons for cessationof cannabis use among these patients. Also, there is limited data on the course of cannabis use in youngschizophrenia patients, the proportion of patients that cease and the moment of cessation.The aim of this study was to describe factors associated with the cessation of cannabis use in a populationof recent onset schizophrenia patients. Data about the moment of starting and quitting cannabis use andthe reason for quitting were collected. We were also interested how many patients experienced their firstpsychotic symptoms after quitting cannabis use. Medical records of 206 patients with schizophrenia orrelated disease who were admitted at the Adolescent Clinic of the Psychiatric Department of the AcademicMedical Centre in Amsterdam were reviewed.Cannabis was the most used substance, 81% had ever used cannabis with 86% of males and 28% offemales. All patients who ever used hard drugs, also had used cannabis. The average amount of jointsused per week was 16,2. The average age of first cannabis use was 15,6 years. The average age ofcessation of cannabis use was 20,4 years. Of all cannabis users, more than half abstained from their use ofcannabis before they were admitted at our clinic. Most patients stopped using cannabis after they becamepsychotic and after their first contact with a caregiver. Almost 50% of quitters said they stopped usingcannabis during a prior admittance for psychosis. A quarter said they stopped after they had experiencedthat cannabis worsened their psychotic symptoms. Three patients had experienced their first psychoticsymptoms after they had stopped using cannabis.Conclusion: Cannabis is the most used drug in this population. Psychosis, outpatient treatment andadmittance for psychosis seems to be associated with patients motivation to stop using cannabis. For fewpatients, psychotic symptoms were experienced after cessation of cannabis.KEY WORDS: Schizophrenia, first episode, cannabis, cessationTELEPHONE-NUMBER: 020-5666289E-MAIL-ADDRESS: nienke.dekker@amc.uva.nl53

TITLERAPHE NUCLEUS ORGANOTYPIC SLICE CULTURE TO STUDY THE SEROTONERGICCONNECTIVITY EX VIVOAUTHORSJeroen J. Dudok, A.J.A. Groffen, P. Voorn, M.P. Witter and M. VerhageDEPARTMENT/INSTITUTEFunctional Genomics/CNCR, VU/VUmc, AmsterdamABSTRACTProper brain function requires a precisely orchestrated connectivity between millions of neurons. After initialassembly, connectivity continues to be modulated by activity (secretion and synapse use). Abnormalalterations in connectivity may result in (psycho)pathological processes contributing to for instance anxietyand depression. Here, we aim to investigate the effect of secretion on the outgrowth of neurites andnetwork formation of the serotonergic system ex vivo.The central serotonin system is a well defined small group of neurons with their cell bodies in the raphenucleus and highly branching projections throughout the brain. To study the connectivity of this system andto characterize the outgrowth of serotonergic fibers, we use organotypic slice cocultures of the raphenucleus and one of its targets such as the hippocampus as a model system. Here we demonstrate that thismodel system can be used to study serotonergic outgrowth and connectivity ex vivo. The organization ofthe serotonergic neurons in the midbrain slice retains the dorsal raphe nucleus topology. Abundantingrowth of serotonergic neurites in the hippocampal slice was observed. These serotonergic neuritescontain numerous varicosities which are synaptotagmin and bassoon positive, suggesting serotonin releasesites. Tryptophan hydroxylase immunoreactivity was also found in these serotonergic varicosities,suggesting local synthesis of serotonin. The growth cones of the serotonergic fibers that invade the targetslice also contain serotonin, suggesting serotonin secretion at the growth cones. The effects of severalserotonergic pharmaca on the outgrowth and connectivity of these neurons is quantified.KEY WORDS: Organotypic, serotonin, outgrowth, connectivity, secretionTELEPHONE-NUMBER: 020-5986931E-MAIL-ADDRESS: jeroen@cncr.vu.nl54

TITLEDISTINCT BEHAVIORAL AND STRUCTURAL BRAIN ABNORMALITIES IN αPix/Arhgef6- DEFICIENTMICEAUTHORSElly van Galen 1 , Kerstin Kuchenbecker 2 , Ellen Kampert 1 , Kerstin Kutsche 2 , Ger J.A. Ramakers 1DEPARTMENT/INSTITUTE1 Neurons and Networks, Netherlands Institute for Neurosciences, Amsterdam ZO; 2 Institut fürHumangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, GermanyABSTRACTMental retardation (MR) is a disorder characterized by an IQ below 70, onset before the age of 18 andsevere limitations in adaptive skills. MR has a high prevalence of 1 to 2 percent, and is the main cause ofinstitutionalization. Nevertheless, still little is known about the underlying mechanisms that cause thisdeficit. We are studying the neurobiological basis of MR by making use of single gene defects, which arefound to cause non-syndromic forms of MR in humans. In these people, the low IQ is the only observablephenotype, and thus the mutated gene is causally involved in the cognitive deficit.Arhgef6, encoding αPix, is one of the, until now about 20, X-linked genes which are found to cause nonsyndromicMR in humans (MRX). αPix is, together with at least two other MRX genes, a regulator of theRho-GTPase signaling pathway. One of the main functions of the Rho-GTPases is regulation of the actincytoskeleton, thereby playing a crucial role in outgrowth, pathfinding and maintenance of axons, dendritesand dendritic spines. Disturbance of this pathway is likely to result in changed neuronal morphology andthereby changed neuronal connectivity and information processing, as seen in MR (Ramakers, TINS 25:191).Arhgef6/αPix has been shown in vitro to activate the Rho-GTPases Rac1 and Cdc42, which are known tostimulate dendritic branching and spine formation. Using a knock-out mouse for Arhgef6/αPix its functionwas studied in vivo. Changes in neuronal network connectivity were studied by quantifying dendriticmorphology and spine densities in hippocampus CA1 after Golgi-Cox impregnation. Unexpectedly,connectivity was found to be rather increased than decreased. Dendritic length and branching wereincreased, as well as the density of mature, mushroom spines.To investigate the effect of the changes on network plasticity, long term potentiation was measured inhippocampus CA1. A significant decrease in LTP was found in the αPix KO mice. Apparently, the network,though more complex, is less adaptive to changes. One possibility to explain this, at first contradictivefinding is that there is a saturation effect in the maturation of the network. Because the amount of maturespines is already increased under normal circumstances, the increase after LTP induction can not be aslarge as in WT.KEY WORDS: Mental retardation, Rho-GTPases, αPix, cognition, morphology, plasticityTELEPHONE-NUMBER: 020-5668967E-MAIL-ADDRESS: e.van.galen@nin.knaw.nl55

TITLEMIMICKING INTRACELLULAR PROTEIN AGGREGATION USING A PEPTIDE-BASED APPRoachAUTHORSJudith M.E.P. Gillis 1 , W.E. Benckhuijsen 2 , J.W Drijfhout 2 , E.A. Reits 1DEPARTMENT/INSTITUTE1) Research Group Protein Degradation and Aggregation, Department of Cell Biology and Histology,Amsterdam Medical Center2) Department of Immunohematology and Blood Transfusion, Leiden University Medical CenterABSTRACTProtein aggregates are a recurring phenomenon in several neurodegenerative diseases such asAlzheimer’s Disease and Huntington’s Disease. While small intermediate aggregates are most likely toxic,the formation of perinuclear aggregates may actually be a protective cellular response. The underlyingmechanism of aggregate formation is poorly understood, because autopsy material from patientsrepresents the end-stage of the aggregation process. To visualize the aggregation process in living cells,we use a peptide-based model which mimics protein aggregation. Fluorescent labeled peptides, which areprotected against degradation, are introduced into cells and start to form aggregates in time. Similar todisease-related protein aggregates, our aggregates travel in a microtubule dependent manner towards theperi-nuclear region of the cell. The main advantage of our model is the usage of peptides instead ofcommonly used vector encoded protein models. Peptides can be chemically modified e.g. fluorescentgroups and tags can be added and length, conformation and sequence can be varied. No expression ofvector encoded proteins is required and aggregation can be immediately followed in time as theseaggregates are formed within six hours upon introduction. As will be shown, peptide aggregation isdependent on intracellular heat shock protein levels and aggregates are transported by dynein motors tothe perinuclear area of the cell. Using this model we want to study why proteins aggregate and identifyproteins that play a role in various stages of protein aggregation.KEY WORDS: Neurodegenerative diseases, protein aggregation, peptide-based model, confocalmicroscopyTELEPHONE-NUMBER: 020-5664974E-MAIL-ADDRESS: j.m.gillis@amc.uva.nl56

TITLEASSORTATIVE MATING FOR OBSESSIVE-COMPULSIVE BEHAVIOR IN A POPULATION-BASEDSAMPLEAUTHORDaniël S. van Grootheest, Stephanie M. van den Berg, Jouke-Jan Hottenga, Daniëlle C. Cath, and Dorret I.BoomsmaDEPARTMENT/INSTITUTEDepartment of Biological Psychology, Vrije Universiteit Amsterdam, AmsterdamABSTRACTBackgroundAssortative mating means that mated pairs are more similar for a phenotypic trait than would be expectedby chance. If a significant marital correlation exists for liability to psychiatric disorders, this should be takeninto account when analysing data from twin and family studies, because the effects may be confoundedwith shared environmental factors. We aimed to test whether there is a significant association for OCbehavior between husbands and wives in a population-based sample. We further evaluated whether maritalresemblance for OC behavior is primary or secondary to assortment for correlated variables.MethodsOC behavior was measured by 12 items of the Padua Inventory Revised. We assessed correlationbetweens twins and their spouses, and between father and mothers of the twins. A model for mateselection addressed whether the correlation between mates for OC behavior arises from direct assortmentor through correlation with other variables for which assortment occurs.ResultsSmall but significant correlations between .1 and .2 for OC behaviour were found between parents of thetwins and between the twins and their partners, indicating that resemblance between spouses does notincrease as a function of duration of marriage. Only a small amount of the observed marital resemblancefor OC behavior could be explained by assortment for correlated variables such as age, religiousattendance and education.ConclusionSmall primary assortment exists for OC behavior. Ignoring this assortment within a twin study only causes anegligible bias.KEY WORDS: OCD, twins, assortative mating, OC behavior, psychiatric geneticsTELEPHONE-NUMBER: 020-5988787E-MAIL-ADDRESS: ds.van.grootheest@psy.vu.nl57

TITLEHIPPOCAMPAL CHANGES IN THE JUVENILE PILOCARPINE MODEL OF TEMPORAL LOBEEPILEPSYAUTHORSW. Saskia van der Hel, Ineke W.M. Bos, Sandra Mulder, Pierre N.E. de GraanDEPARTMENT/INSTITUTERudolf Magnus Institute of Neuroscience, Dept. of Pharmacology and Anatomy, University Medical CentreUtrecht, UtrechtABSTRACTTemporal lobe epilepsy (TLE) is a common form of epilepsy in which seizures arise from the temporal lobe.TLE normally develops after a precipitating injury early in life. Several mechanisms have been implicated inthe pathogenesis of this disease, such as changes in the metabolism of the main excitatoryneurotransmitter glutamate, but also alterations in the metabolism of the principal inhibitoryneurotransmitter of the brain γ-amino butyric acid (GABA). To study the process of epileptogenesis, animalmodels have to be used. The lithium-pilocarpine model is a status epilepticus (SE) model in the ratcommonly used to study aspects of human TLE. SE is one of the initial lesions that can induce TLE. Wetherefore used a juvenile model to resemble the human situation. The present study was designed to studyseveral elements that might be involved in the process of epileptogenesis in the hippocampus of thejuvenile pilocarpine rat model.SE was induced at P21 with a moderate dose of pilocarpine (40 mg/kg). Rats were killed at different timepoints:2, 4, 8 or 19 weeks after induction of SE (+SE). Neuronal damage was visualized with FluoroJade(FJ) staining. The hippocampal distribution of several elements involved in the gaba-ergic (glutamic aciddecarboxylase (GAD) which converts glutamate into GABA and parvalbumin (PV) which represents aspecific subpopulation of GABAergic interneurons) or glutamatergic pathway (glutamine synthetase (GS)which converts glutamate into the non-toxic glutamine) was examined by immunohistochemistry in +SE andcontrol animals.FJ staining showed damaged neurons in the hilus of the hippocampus, most prominent at 2 weeks afterpilocarpine induced SE. In the same region of these +SE animals, significant loss of PV containing neuronswas found, not only 2 weeks, but also 4, 8, and 19 weeks after SE, whereas GAD IR was upregulated 2and 4 weeks after pilocarpine induced SE. GS IR on the other hand was significantly reduced in +SEanimals, with a maximum reduction 19 weeks after pilocarpine induced SE.These data indicate that especially the hilus of the hippocampus is very vulnerable for pilocarpine inducedSE at a young age. Loss of neurons, among which PV containing interneurons, is already found early afterthe induction of SE. However, the overall interneuron population (GAD) was increased at this time-point.This can be a compensatory mechanism for the loss of other interneurons or an upregulation of GAD insurviving neurons. It seems that the glutamatergic pathway, here visualized only by the glial enzyme GS, isdownregulated at a later time-point, which thus might be a consequence of changes, e.g. neuronal death,that already have occurred. These data are in agreement with data from human studies, thereby indicatingthat this juvenile pilocarpine model is a good model to study the process of epileptogenesis.KEY WORDS: Temporal lobe epilepsy, pilocarpine, status epilepticus, glutamatergic neurotransmission,gaba-ergic neurotransmission, epileptogenesisTELEPHONE-NUMBER: 030-2538329E-MAI-ADDRESS: w.s.vanderhel@med.uu.nl58

TITLESUSCEPTIBILITY GENES FOR SPORADIC FEBRILE SEIZURESAUTHORSEllen Hessel, Koen van Gassen, Inge Wolterink, Martien Kas en Pierre de GraanDEPARTMENT/INSTITUTERudolf Magnus Institute, UtrechtABSTRACTFebrile seizures (FS), which are the most common seizure types in children, affect about five percent ofchildren. Complex FS may be involved in the development of temporal lobe epilepsy (TLE) duringadulthood, but the underlying mechanism of FS remains unknown. There are two types of FS: familiar andsporadic FS. Recent association, family and twin studies indicate that genetic background is important inFS. Therefore, identification of FS susceptibility genes is relevant to understand the molecular mechanismunderlying FS and their relationship with TLE. The aim of this study is to identify FS susceptibility genesand cascades using a panel of mouse chromosome substitution strains.Complex febrile seizures were induced in the host (C57) and donor (A/J) strain of the panel byhyperthermia by exposure to a 50 0 C air stream for 900s at postnatal day 14. During this period mousebehavioral repertoire and body temperature were continuously monitored. The two most reliable behavioralphenotypes characteristic for the onset and the expression of seizures was found to be immobility followinghyperthermia induced mobility and clonic-tonic convulsions combined with loss of posture. Using theseparameters we found that C57 have an immobility latency of 172.5 ± 8.2 and a clonic-tonic convulsionslatency of 587.6s ± 26, whereas A/J mice have latencies of 275.4s ± 40 and >900s respectively. Thus C57mice are more susceptible to hyperthermia-induced seizures that A/J mice. Therefore the chromosomesubstitution panel is suitable to search for febrile seizure susceptibility genes and cascades. Presently weare screening the complete panel to identify the chromosomes carrying the quantitative trait loci for febrileseizures.KEY WORDS: Febrile seizures, chromosome substitution strains, hyperthermiaTELEPHONE-NUMBER: 030-2538845E-MAIL-ADDRESS: e.v.s.hessel@med.uu.nl59

TITLEMUTATION SCREENING OF THE SCGE GENE IN OBSESSIVE-COMPULSIVE DISORDER ANDTOURETTE SYNDROMEAUTHORSHilga Katerberg 1,2 , D. Cath 3 , M. A. J. Tijssen 4 , E. M. J. Foncke 4 , Y. van de Leemput 5 , J. A. den Boer 2 , P.Heutink 1,6 , F. Baas 5,4DEPARTMENT/INSTITUTE1 Department of Human Genetics, Section Medical Genomics, VU University Medical Center, Amsterdam;2 Department of Biological Psychiatry, University Medical Center Groningen, University of Groningen,Groningen; 3 Department of Psychiatry, VU University, Amsterdam,; 4 Department of Neurology, AcademicMedical Center, Amsterdam; 5 Department of Neurogenetics, Academic Medical Center, Amsterdam;6 Center for Neurogenomics and Cognitive Research, VU University Medical Center and VU University,AmsterdamABSTRACTMutations in the epsilon sarcoglycan gene (SGCE gene) are associated with obsessive-compulsivebehavior in some families with Myoclonus-Dystonia (M-D). Therefore, we screened the SGCE gene formutations in patients with Obsessive-Compulsive Disorder (OCD) and/or Gilles de la Tourette syndrome(GTS), a genetically related tic-disorder.We screened the coding region and flanking intronic regions of the SGCE gene for mutations in 88 patientswith OCD and/or GTS with a positive family history for tics and/or obsessive-compulsive behavior and 5patients with non-familial OCD. No sequence variants were found in the coding region of the SGCE geneand several common polymorphisms were present in the intronic regions of the SGCE gene. However, weidentified three new sequence variants in the 3’UTR of the SGCE gene. These variants are predicted to bewithin putative microRNA binding sites and could have a biological function. Two of these sequencevariants were not present in control chromosomes from the general Dutch population. The third variant wasnot present in the control chromosomes and segregated with GTS but not with OCD. Future studies toinvestigate the significance of this variant are warranted.KEY WORDS: Epsilon Sarcoglycan gene, Tourette syndrome, Obsessive-Compulsive DisorderTELEPHONE-NUMBER: 020-5987025E-MAIL-ADDRESS: h.katerberg@vumc.nl60

TITLEINSTRUMENTAL ASSESSMENT OF TONGUE DYSKINESIAAUTHORSJeroen P.F. Koning, P.N. van HartenDEPARTMENT/INSTITUTEUMC Utrecht / Psychiatry, UtrechtABSTRACTBackgroundDyskinesia is a severe and disabling movement disorder that affects approximately 20% of schizophrenicpatient who use antipsychotics. Therefore it is an important element of attention in psychiatric care.Dyskinesia of the tongue is most frequently assessed by the Abnormal Involuntary Movement Scale(AIMS). The scoring of the AIMS however is dependent on experience and bias of the raters (interraterreliability) and could be underestimated in presence of slight movement disorders (Sensitivity). Wehypothesise that the use of instrumental measurement of dyskinesia may overcome these limitations.Therefore we developed an instrument to measure tongdyskinesiaAimValidate a technique to quantify tong instability by using an instrument.MethodSeven healthy subject and twenty-four patients (ten without and fourteen with tongdyskinesia) meetingDSM-IV criteria for schizophrenia were included. All subjects were screened for movement disorders andvideotaped. The videos were used to assess the severity of dyskinesia by consensus by 2 experts in thefield of movement disorders. Dyskinesia of the tongue was instrumental measured by exerting a constantpressure on a load cell. The lingual instability could be quantified. We compared the clinical movementrating scales with instrumental measurements.ResultsWe are currently analysing and will report the results at the congress.DiscussionInstrumental measurement of tongue dyskinesia could advance objective and sensitive diagnosis. Ittherefore could be used for screening dyskinesia in an early stageTELEPHONE-NUMBER: 030-2509921E-MAIL-ADDRESS: jpf.koning@symfora.nl61

TITLESUPEROXIDE DISORGANIZES BRAIN ENDOTHELIAL CYTOSKELETON VIA PI 3-KINASEAUTHORSGijs Kooij*, Gerty Schreibelt*, Linsay Grijpink-Ongering**, Christine Dijkstra*, Eric Ronken**, Elga de Vries*.DEPARTMENT/INTITUTE*Department of Molecular Cell Biology, VU Medical Center, Amsterdam; **Solvay PharmaceuticalsResearch Laboratories, WeespABSTRACTMigration of monocytes across the blood-brain barrier (BBB) is a critical step in the development ofinflammatory lesions during multiple sclerosis (MS). Transendothelial migration of monocytes requires theactive participation of brain endothelial cells (BEC); they need to rearrange their cytoskeleton and tightjunctions via intracellular signalling events. Previously we showed that reactive oxygen species (ROS) areessential for monocyte migration and that superoxide is the pertinent ROS that affects the integrity of theendothelial cell layer.To identify underlying mechanisms, we here investigated the signalling events after ROS treatment ofcultured BEC. Our results show that superoxide treatment in time results in phosphorylation of proteinkinase B (PKB), which is a downstream target of PI 3-kinase. In addition, other signalling moleculesinvolved in cytoskeletal rearrangements (Rho, Ca 2+ and PKC) mediate this superoxide-induced PKBphosphorylation. This activation of PKB can be inhibited in the presence of anti-oxidants, such as lipoic acidand luteoline. Using life cell imaging techniques we have quantified superoxide-induced changes in theactin cytoskeleton. These cytoskeletal changes could be prevented by the PI 3-kinase inhibitor wortmannin.This study shows that oxygen radicals, in particular superoxide, activate PI 3-kinase pathways in culturedBEC and that PI 3-kinase activity is involved in ROS induced cytoskeletal rearrangements. Elucidation ofsignalling events that mediate cellular migration across the brain endothelium may lead to new therapeuticstrategies for the treatment of MS.KEYWORDS: Multiple Sclerosis, blood-brain barrier, reactive oxygen species, PI3-kinaseTELEPHONE NUMBER: 020-4448059E-MAIL-ADDRESS: g.kooij@vumc.nl62

TITLEHYPOTHALAMIC ABNORMALITIES AND GENETIC RISK IN TWINS DISCORDANT FORSCHIZOPHRENIAAUTHORSCédrick (P.C.M.P.) Koolschijn, M.S.; Hulshoff Pol HE, PhD; Van Haren NEM, PhD; Kahn RS, Prof. MDDEPARTMENT/INSTITUTESection Structural Neuroimaging, Dept. of Psychiatry , RMI UtrechtABSTRACTBackgroundThe hypothalamus, part of the Hypothalamus-Pituitary-Adrenal-axis, is involved in stress regulation,emotions and reproduction. Except for the latter, these behaviors and physiological systems have beenimplicated in schizophrenia. However, it remains unknown if there are differences in hypothalamus volumesbetween patients and healthy controls and if so whether these changes are related to genetic orenvironmental risk factors for schizophrenia.MethodsTwin studies in schizophrenia are particularly informative to examine the relative contribution of genetic andenvironmental risk factors in brain volume changes reported in this illness. Using structural magneticresonance imaging, hypothalamus volumes in 22 monozygotic and dizygotic twin pairs discordant forschizophrenia were measured and compared to those in 22 healthy comparison twin pairs.ResultsWithin-twin pair similarities of hypothalamus volume were higher in monozygotic than in dizygotic twin pairs,and volumes of the hypothalamus were smaller in both members of the discordant twin pairs.ConclusionsThe results suggest that hypothalamus volume is partly under genetic control. It may be possible that genesinvolved in hypothalamus volume are also involved in the genetic vulnerability to develop schizophrenia.KEY WORDS: Schizophrenia, twins, hypothalamus, discordant, genetic risk, magnetic resonance imaging,morphologyTELEPHONE-NUMBER: 030-2501783E-MAIL-ADDRESS: p.c.m.p.koolschijn@umcutrecht.nl63

TITLECYTOARCHITECTONIC ABNORMALITIES IN THE TEMPORAL FUSIFORM GYRUS IN AUTISTICPATIENTSAUTHORSImke A.J. van Kooten 1,2,3 , H. Heinsen 4 , P.R. Hof 5 , H. van Engeland 1 , H.W.M. Steinbusch 2,3 ,C. Schmitz 2,3DEPARTMENT/INSTITUTE1 Department of Psychiatry and Neuropsychology, Division of Cellular Neuroscience, Maastricht University,Maastricht; 2 European Graduate School of Neuroscience (EURON), Maastricht; 3 Rudolf Magnus Institute ofNeuroscience, Department of Child and Adolescent Psychiatry, University Medical Center Utrecht, Utrecht;4 Morphological Brain Research Unit, University of Wuerzburg, Wuerzburg, Germany; 5 Department ofNeuroscience, Mount Sinai School of Medicine, New York, NY, USAABSTRACTAutism is a severe neurodevelopmental disorder characterized by social deficits, language abnormalitiesand stereotyped repetitive behavior. In addition, face processing, a primary feature of human socialinteraction, is impaired in autism. Magnetic Resonance Imaging (MRI) studies have reported abnormalactivation of the temporal fusiform gyrus (TFG) in autistic patients. However, the underlying cellular andmolecular mechanisms remain to be established. The present study investigated mean total- and layerspecificvolume, mean total neuron number and mean perikaryal size of neurons in layer V of the TFG inthe brains of 7 autistic patients (DSM-IV and ADI) and 10 matched controls. Entire brain hemispheres wereembedded in celloidin and cut into series of 200-µm-thick frontal sections that were stained withGallocyanin. No significant differences were found between the autistic patients and the controls withrespect to mean total volume, mean layer-specific volumes and the mean total neuron number in layer V ofthe TFG. However, there was a trend towards a volume decrease of layer V of the TFG. The meanperikaryal size of layer V neurons in the TFG was significantly smaller (-26%, p

TITLECAUDATE NUCLEUS IS ENLARGED IN HIGH-FUNCTIONING MEDICATION-NAIVE SUBJECTS WITHAUTISMAUTHORSMarieke Langen, Sarah Durston, Wouter G. Staal, Saskia J.M.C. Palmen and Herman van EngelandDEPARTMENT/INSTITUTEDepartment of Child and Adolescent Psychiatry, Rudolf Magnus Institute of Neuroscience, UniversityMedical Center UtrechtABSTRACTContextOne of the three defining symptom-clusters of autism is repetitive and stereotyped behavior. Neuroimagingand laboratory studies have implicated the basal ganglia, and in particular the striatum, in the developmentof repetitive behaviors in multiple neuropsychiatric disorders. Subjects with autism are often treated withneuroleptic medication, known to affect basal ganglia volumes. As such, magnetic resonance studies ofbasal ganglia structures in autism are typically not able to separate the effect of treatment from effects moredirectly related to the disorder.ObjectiveTherefore, we set out to investigate basal ganglia structures in subjects with autism who had never beenmedicated.DesignCross-sectional design comparing volumetric magnetic resonance measures of caudate nucleus, putamenand accumbens nucleus in two independent samples of medication-naive subjects with autism andmatched controls.SubjectsTwo independent samples were included: 1) twenty-one medication-naïve, high-functioning children andadolescents with autism or Asperger’s syndrome and 21 matched controls and 2) twenty-one medicationnaïve,high-functioning older adolescents and young adults with autism or Asperger’s syndrome and 21matched controls. In both samples, affected subjects and normally developing controls were matched forage, gender, IQ, height, weight, handedness, and parental education.MethodsThe volumes of caudate nucleus, putamen and accumbens nucleus were reliably estimated from magneticresonance images using a strict measurement protocol, as were total brain and intracranial volumes. Basalganglia structures were traced manually by a single experienced rater (ML). Intrarater reliability wasestimated using intraclass correlation coefficients (ICCs). ICC-scores were 0.99 for caudate nucleusvolume, 0.96 for putamen and 0.97 for accumbens nucleus.ResultsResults were similar in both independent samples. Caudate nucleus was significantly enlarged (p=.008 insample 1; p=.001 in sample 2). This result remained significant after correction for total brain or intracranialvolume. Enlargements in other basal ganglia structures were proportional to an overall increase in brainvolume.ConclusionsThese results implicate the caudate nucleus in the etiology of autism, as an increase in the volume of thisstructure, disproportional to an overall increase in total brain volume was found in two independent samplesof medication-naive subjects with autism.KEY WORDS: Autism, neuro-imaging, basal ganglia, repetitive behaviorTELEPHONE-NUMBER: 030-2507084E-MAIL-ADDRESS: m.langen@umcutrecht.nl65

TITLEFIRING ACTIVITY IN THE RAT MEDIAL PREFRONTAL CORTEX DURING CHANGES IN STIMULUSRELEVANCEAUTHORSEunjeong Lee, Henrique Cabral, Cyriel M. A. PennartzDEPARTMENT/INSTITUTEAnimal Physiology and Cognitive Neuroscience, Center for Neuroscience, Swammerdam Institute for LifeSciences, University of Amsterdam, AmsterdamABSTRACTSwitching attention upon changing environmental demands is an essential characteristic of cognitiveflexibility. Not surprisingly, Attentional Set Shifting (ASS) has been found to be impaired in schizophrenia,autism, attention deficit/ hyperactivity disorder (ADHD) and personality disorders.ASS might be encoded by medial prefrontal cortex (mPFC) neurons and appears to be a dynamic functionof specialized neural networks incorporating mPFC. In order to understand neural mechanisms of ASS, wehave investigated ensemble coding strategies of neurons in the prefrontal cortex of freely moving rats byusing a multi-electrode (tetrode) recording technique under a hypothesis that mPFC neurons encode anumber of task-relevant attributes, such as modality-specific attributes of stimuli with a dominantrepresentation of the relevant sensory dimension such as reward predicting, rules and goal-directedactions.We designed a multimodal discrimination task set in a chamber where visual, odor and sound stimuli couldbe presented to the rat in a time-controlled manner. The chamber was equipped with an odor port, aspeaker and a visual screen, while a reinforcement tray was situated in the rear of the cage. The learningtask required that once the trial onset light turned on, the rat had to put its head in the port of the chamber,where stimuli were simultaneously presented (e.g. rose odor or/and a visual pattern). All sessions startedwith a simple discrimination (SD) protocol which was two exemplars in same dimension used – relevantone. If the rat reached criteria, the task shifted to a compound discrimination (CD) protocol which was newtwo exemplars in different dimension – irrelevant one - added to the previous one, however the rat wasrequired to keep discriminating between different stimuli in the relevant dimension. After this stage, ratswere subjected to reversal learning (reverse the reinforcement values) and other tasks (such as, IntraDimensional Shifting (use new exemplars) and Extra Dimensional Shifting (reverse the dimensions))requiring flexible switching in single or consecutive sessions (see Birrell and Brown, J. Neurosci. 20(2000),4320-4324, for a comparable behavioral task).855 units were recorded in the mPFC from 3 rats and only 207 units have been analyzed until now. 25.1 %of which was correlated to the task. Specifically, 4.3 % of the task related units was correlated topresentation of stimuli, 5.3 % to reinforcement delivery and 13 % to post-stimulus actions (p-value < 0.05with KS test). Single trial analysis is used for detecting similarity and distractibility of neural firing rate aftershifting each state.KEY WORDS: Attentional set shifting, multimodal discrimination, multi electrode recordingTELEPHONE-NUMBER: 020-525-7674,E-MAIL-ADDRESS: elee@science.uva.nl66

TITLETHE ROLE OF THE TRANSCRIPTION FACTOR Nfil3/E4BP4 IN NEURONAL REGENERATIONAUTHORSHarold D. Mac Gillavry*, F.J. Stam*, J. Verhaagen**, A.B. Smit*, R.E. van Kesteren*DEPARTMENT/INSTITUTE*Dept of Molecular and Cellular Neurobiology, Vrije Universiteit, Amsterdam, **WorkgoupNeuroregeneration, Netherlands Institute for Brain Research, AmsterdamABSTRACTSuccessful regeneration after nerve injury depends on both the environmental circumstances and theintrinsic growth capacity of the damaged neurons. The intrinsic capacity of neurons to regenerate probablydepends on their ability to express regeneration-associated genes. In a previous micro array experiment inour group, gene expression profiles of dorsal root ganglion (DRG) neurons were determined afterperipheral sciatic nerve crush and after central dorsal root crush. In this way genes regulated duringsuccessful regeneration, i.e. after a peripheral crush, could be distinguished from genes regulated after acentral nerve crush, which does not lead to successful regeneration. Interestingly, among the earlyregulatedgenes we found a large set of transcription factors. We now focus on this group of genes, whichwe believe are critical in the coordination of the downstream transcriptional network regulating neuronalregeneration. Currently, we employ a siRNA-mediated screen to identify which of these regulatedtranscription factors are involved in neurite outgrowth. Of these, knockdown of Nfil3/E4BP4 results in amarked increase of neurite outgrowth. This is however not consistent with its up regulation found duringsuccessful regeneration. Thereby, Nfil3/E4BP4 over expression also induces increased neurite outgrowth.This might point to an important dual role of Nfil3/E4BP4 as a transcriptional regulator of neurite outgrowth.To better understand these unexpected results and learn more on the role of Nfil3/E4BP4 as atranscriptional regulator we now use chromatin immunoprecipitation to analyze its direct transcriptionaltargets.KEY WORDS: Regeneration ; transcription factor ; gene expression ; chromatin immunoprecipitation ;transcriptional regulatory networkTELEPHONE-NUMBER: 020-5987122E-MAIL-ADDRESS: harold.macgillavry@falw.vu.nl67

TITLECROSSMODAL INTEGRATION OF EMOTIONAL FACES AND VOICES IN PERVASIVEDEVELOPMENTAL DISORDER: AN ERP STUDYAUTHORSMaurice J.C.M. Magnée a,b , Beatrice de Gelder b,d , Herman van Engeland a and Chantal Kemner a,cDEPARTMENT/INSTITUTEaRudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center, Utrecht; bLaboratory of Cognitive and Affective Neuroscience, Tilburg University, Tilburg; c Section BiologicalDevelopmental Psychology, Faculty of Psychology, Maastricht University, Maastricht;dMartinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School,Charlestown, Massachusetts 02129, USAABSTRACTPervasive developmental disorder (PDD) refers to a group of behavioral disorders of which autism is themost severe. Lack of social and emotional reciprocity counts among the most characteristic social-cognitiveimpairments of autism and has for example been well documented for processing facial expressions. Herewe investigated to what extent a deficit in recognition of facial expressions is associated with abnormalintegration between the emotion seen in the face and heard in the voice. Electrophysiological responses tofacial expressions and to face-voice pairs which were either emotionally congruent or incongruent weremeasured in adult PDD patients and matched controls. Increased P1 and N170 amplitudes were seen inresponse to the presentation of fearful faces as compared to happy faces in both groups. These resultsindicate normal processing of facial expressions among PDD patients. ERP responses to audiovisualpresentation showed increased occipito-temporal amplitudes in response to fearful voices at 200 ms, onlywhen presented in combination with a fearful face. This effect was observed in the control group, but not inthe patient group. Because of the importance of rapid audiovisual integration of emotional information onsocial competence, the absence of such modulation in PDD might attribute to the observed deficits in theiremotional behavior.KEY WORDS: Autism, emotion, multisensory integration, Event-Related PotentialsTELEPHONE-NUMBER: 030-2506026E-MAIL-ADDRESS: m.j.c.m.magnee@umcutrecht.nl68

TITLEEPILEPSY SURGERY IN CHILDREN: IMAGING PLASTICITY OF MEMORYAUTHORJoost MeekesDEPARTMENT/INSTITUTEDepartment: Neurology/Neuropsychology, University Medical Center Utrecht - Wilhelmina Children'sHospital/Rudolf Magnus Institute of Neuroscience, Utrecht UniversityABSTRACTChildren often show remarkable functional plasticity after brain injury, recovering functions which in an adultwith a similar lesion would be forever lost. However, the cerebral changes underlying this functionalplasticity are not well-understood. For example, it is not known to what extent differences in functionalplasticity between children are related to differences in cerebral plasticity. We attempt to contribute tounderstanding the relation between functional and cerebral plasticity using paediatric epilepsy surgery as amodel.Eight temporal lobectomy patients will complete an fMRI memory protocol before and six months aftersurgery. Eight age- and gender-matched controls will be scanned at the same interval. Both groups will alsoundergo a full neuropsychological assessment at both points. Our main questions:- Are there changes in patterns of brain activation during memory tasks over time (controls)?- Do these changes differ from those in patients and if so, how (patients vs controls)?- Are the changes in brain activation patterns resulting from resection related to performance atneuropsychological assessment (patients)?KEY WORDS: Epilepsy, memory, fMRI, plasticityTELEPHONE-NUMBER: 06-16504531E-MAIL-ADDRESS: j.meekes@umcutrecht.nl69

TITLEGFAP ISOFORMS IN BRAINS OF ALZHEIMER PATIENTS AND NON-DEMENTED CONTROLSAUTHORSJinte Middeldorp, R.F. Roelofs, J.A. Sluijs, T. Bets, N. Postma, E.M. HolDEPARTMENTDept. Cellular Quality Control, Netherlands Institute for Neuroscience, KNAW, AmsterdamABSTRACTGlial fibrillary acidic protein (GFAP) is an intermediate filament protein type III and considered to be a highlyspecific marker for glia. The human GFAP gene is known to generate multiple splice variants. Thecanonical form is GFAPα and previously also a β and γ isoform were reported. Recently our group hasidentified four novel splice variants of GFAP: ∆135, ∆164, ∆exon 6 and δ.Strikingly, the expression of the out-of-frame ∆164 and ∆exon6 splice variants, studied with a specificantibody (GFAP+1), was observed in a subpopulation of degenerating neurons in the hippocampus ofAlzheimer patients. Although an increased GFAP expression due to astrogliosis is a well known hallmark ofAD pathology, the observation of GFAP expression in degenerating neurons was an unexpected finding.Furthermore, an antibody against the GFAPδ protein revealed expression of this isoform specifically in asubpopulation of astrocytes in the subventricular zone and the subpial zone of the human cerebral cortex.These results suggest that GFAPδ is a marker for a subpopulation of neural progenitor cells, which areknown to reside in these areas.To further study the expression of the different GFAP isoforms, including GFAPα, we assembled a set ofantibodies that enable us to discriminate between the different isoforms in immunohistochemical stainingsof human brain material. These antibodies were characterized on Western blot on isolated filaments fromhuman spinal cord and on recombinant GFAPα, δ and ∆135.Recently, we discovered that both neurons and astrocytes express various GFAP isoforms and surprisingly,not all astrocytes express GFAPα. To further specify the different cell types that express the GFAPisoforms, co-localisation studies are being performed. Future studies are focused on the function of thedifferent isoforms in these cell types, in control and Alzheimer brains.KEY WORDS: GFAP, Alzheimer, HippocampusTELEPHONE-NUMBER: 020-5665515E-MAIL-ADDRESS: j.middeldorp@nin.knaw.nl70

TITLEFINDING GENES INVOLVED IN AVOIDANCE AND APPROACH BEHAVIOUR USING CHROMOSOMESUBSTITUTION STRAINSAUTHORSAnnetrude (J.G.) de Mooij-van Malsen 1 , M. de Krom 1 , B. Olivier 1,2 , H. van Lith3, K. van Gassen 1 ,H. Oppelaar 1 , J. Hendriks 1 , M. de Wit 1 , F.C.P. Holstege 4 , B.A. van Oost 3 , P.N. de Graan 1 , and M.J.H.Kas 1DEPARTMENT/INSTITUTE1Rudolf Magnus Institute of Neuroscience, Behavioral Genomics Section, University Medical CentreUtrecht; 2 Department of Psychopharmacology, University Utrecht; 3 Department of Animal, Science andSociety, University Utrecht; 4 Department of physiological Chemistry, University Medical Centre UtrechtABSTRACTAnxiety disorders have a powerful effect on the lives of many people. Finding the mechanisms underlyingthese disorders is of crucial meaning to develop proper treatment.In an animal, the balance between avoidance and approach behaviour is an element of the level of anxietyit expresses.Standard behavioural experiments such as the open field and elevated plus maze are short lasting andsubject to a lot of interference. By exposing the animal to a modified homecage environment in a multi dayrecording and examining the preference for a “saver” or more “exposed” feeding platform, we can findchanges in anxiety level separate from locomotor activity in strains of mice. Both novelty induced andbaseline behaviour can then be compared.We tested a complete chromosome substitution strain (CSS) panel in this setup. This panel consists of 21strains of mice. Within each strain 1 whole chromosome of the host strain (C57BL/6J) has been substitutedby a chromosome of the donor strain (A/J). A phenotypical difference found within a CSS is caused by aquantitative trait locus on that particular chromosome.A strain of interest was selected this way and a backcross-intercross F2 population created. By combininggenetic mapping, microarray studies and in situ hybridization, we were able to find a gene involved in motoractivity. We are now further investigating the role of this gene and the pathways involved in the nervoussystem. Further, we have tested the F2 population of a strain of which we hypothesize that it carries a QTLinvolved in avoidance behaviour.KEYWORDS: Avoidance, approach, genes, chromosome substitution strains, motor activity, home cageenvironment, multi day recordingTELEPHONE-NUMBER: 030 253 8845E-MAIL-ADDRESS: j.g.demooij-vanmalsen@med.uu.nl71

TITLEPREVENTION OF DEPRESSION AND SLEEP-DISTURBANCES IN ELDERLY WITH MEMORY-PROBLEMS; ACTIVATION OF THE BIOLOGICAL CLOCK WITH LIGHTAUTHORSEls Møst and E. van SomerenDEPARTMENT/INSTITUTESleep and cognition; Netherlands Institute for Neuroscience, KNAW, AmsterdamABSTRACTSleeping problems and depression are frequent among demented elderly and primary reasons forinstitutionalizing. Both may in part be related to a reduced function of the SCN. We hypothesize that SCNfunctionality can be enhanced by additional light. An earlier study in 190 demented elderly showed thatprolonged exposure to additional light reduced sleep problems and depression, and ameliorated thecognitive decline.The present randomized clinical trial investigates whether light treatment has similar positive effects inhome-dwelling elderly whose neurodegeneration is still in the earliest phases in an. The primary goal is toinvestigate whether two years of daily exposure to bright light will ameliorate or prevent depressivesymptoms.Subjects diagnosed with subjective memory problems, mild cognitive impairment (MCI) or Alzheimerdisease (AD) (mmse >17) are invited to participate. All subject are IADL independent at intake and have nodiagnosed other neurological or psychiatric disorders.Following a baseline measurement, active (10 000 lux) or placebo (350 lux) light will be installed in theparticipant’s home. Four effect measurements with an interval of half a year are planned.Measurements include (1) actigraphic sleep and activity rhythm assessment; (2) questionnaires regardingsleep (Athens, SDL and Pittsburg) and depression (GDS); (3) 24hr recordings of skin temperature, heartrate and hormone levels (melatonin and cortisol, sampled from saliva) and (4) neuropsychologicalassessment for evaluation of the decline in cognitive abilities.We expect that active light will reduce depressive symptoms and stabilize sleep cycles. We secondarilyexpect the treatment to reduce the cognitive decline. Analyses will furthermore evaluate the relation ofcircadian rhythms in activity, cortisol, melatonine, heart rate and temperature to depression and sleep.KEY WORDS: Light therapy, neurodegeneration, circadian rhythms, depression, sleepTELEPHONE-NUMBER: 020-4443570 / 020-5665488E-MAIL-ADDRESS: e.most@nin.knaw.nl72

TITLEGENETIC RISK FOR ADHD IN BRAIN FUNCTIONINGAUTHORSMartijn J. Mulder 1 , D. Baeyens 1, 3 , M.C. Davidson 2 , B.J. Casey 2 , E. van der Ban 1 , H. van Engeland 1 ,S. Durston 1, 2DEPARTMENT/INSTITUTE1 Rudolf Magnus Institute of Neuroscience, Department of Child and Adolescent Psychiatry, UniversityMedical Center Utrecht, Utrecht; 2 Sackler Institute for Developmental Psychobiology, Weill Medical Collegeof Cornell University, New York, USA; 3 Department of Psychology, Developmental Disorders, Faculty ofPsychology and Educational Sciences, Ghent University, Ghent, BelgiumABSTRACTAttention-Deficit/Hyperactivity Disorder (ADHD) is a developmental neuropsychiatric disorder where familialeffects significantly contribute to susceptibility for the disorder. Evidence from twin and adoption studiesindicates that genetic effects explain 80% of the phenotypic variance in ADHD. Siblings of children withADHD have a three- to fivefold increase in risk for developing the disorder. Although several genes havebeen associated with the disorder, the genetic background of ADHD is likely to be complex and the effect ofany single gene is therefore probably modest.In order to determine whether increased familial risk for ADHD is associated with differential patterns ofbrain activation compared to typically developing children, we have designed tasks to probe cognitivefunctions that are compromised in ADHD. We are focusing on inhibitory control, and the related ability tobuild up expectations about the environment. In a recent functional MRI study we used a go/no-go taskwhere we manipulated task difficulty to investigate inhibitory control. Compared with healthy controls, bothsubjects with ADHD and their unaffected siblings showed decreased activation in the neural networkunderlying this ability, suggesting a genetic vulnerability for ADHD in these regions. As such, brainactivation associated with inhibitory control may be a potential endophenotype for ADHD.Currently we are using a task where we violate temporal and stimulus expectations. Since informationabout what to expect and when to expect it is critical for planning and maintaining actions, an impairedability to detect violations of expectation may lead to inappropriate and disruptive behaviors associated withthe disorder. I will discuss this study in more detail in my poster presentation.KEY WORDS: ADHD, Neuroimaging, development, functional MRI, inhibition, expectation, endophenotypeTELEPOHONE-NUMBER: 030-2509840E-MAIL-ADDRESS: m.mulder-7@umcutrecht.nl73

TITLEA LONGITUDINAL STRUCTURAL MRI-STUDY OF ADOLESCENCE IN HIGH-FUNCTIONING AUTISMSPECTRUM DISORDERS: PRELIMINARY EVIDENCE OF PROGRESSIVE CHANGEAUTHORSHilde Nederveen, Bertine Lahuis, Saskia Palmen, Tim Ziermans, Herman van Engeland, Sarah DurstonDEPARTMENT/INSTITUTENeuroimaging Lab, Department of Child and Adolescent Psychiatry, Rudolf Magnus Institute ofNeuroscience, University Medical Centre UtrechtABSTRACTIntroductionAutism is a severe developmental disorder associated with an approximate increase of 5% in brain volumein young children with autism spectrum disorders (ASD). However, results in adolescents and adults aremore controversial. Whereas some studies report that brain enlargement reverts to the normal range duringadolescence (e.g., Aylward et al., 2002) others have still shown increased brain volumes in adolescentsand adults with ASD (Palmen et al., 2004; Piven et al., 1995). Here, we employ a longitudinal design toinvestigate whether brain enlargements persist during adolescence in individuals with ASD.MethodsData from 36 children were included in this first analysis. This included fifteen children with ASD, tenchildren with an autism spectrum diagnosis, MCDD and eleven matched, typically developing children. Allsubjects were scanned twice in order to investigate brain development during adolescence. On average, allgroups were 10,8 years at the time of scan 1 and 14,6 years at the time of scan 2. All groups were matchedfor age at first scan, age at second scan, time between scans, gender, IQ and handedness.Semi-automated volumetric measurements of intracranium, total brain, cerebellum, lateral and thirdventricles, grey and white matter were acquired.ResultsPreliminary results show a significant difference in rate of ventricular growth (volume change per year) inchildren with ASD compared to controls (p ≤ .05).ConclusionThe significant difference in ventricular growth suggests that progressive changes are ongoing in childrenwith ASD during adolescence. The rate of change in total brain volume was not significantly differentbetween the groups, although this may be related to limited power in this relatively small sample. Follow-upinvestigations will include measuring the volume of structures surrounding the ventricles (the basal gangliaand medial temporal lobe structures) and increase in the sample to a total of 50 children with ASD and 50healthy controls.References:Aylward et al. (2002) Effects of age on brain volume and head circumference in autism. Neurology 53:2145-2150Palmen et al. (2004) Larger brains in medication-naïve high-functioning adolescents with PervasiveDevelopmental Disorder. Journal of Autism and Developmental Disorder 34:603-613Piven et al. (1995) An MRI study of brain size in autism. Am.J.Psychiatry 152:1145-1149TELEPHONE NUMBER: 030-2509840E-MAIL-ADDRESS: h.nederveen@umcutrecht.nl74

TITLEMOLECULAR PLASTICITY AT THE SYNAPSE RESULTING FROM HEROIN ABSTINENCE ANDREINSTATEMENT OF HEROIN SEEKING BEHAVIORAUTHORSMichel C. van den Oever, K.W. Li, T.J. de Vries*, A.N.M. Schoffelmeer*, A.B. Smit, S. SpijkerDEPARTMENT/INSTITUTEDept. of Molecular and Cellular Neurobiology, Vrije Universiteit, Amsterdam; *Dept. of Anatomy andNeuroscience, VU University medical center, AmsterdamABSTRACTOne of the prime problems with addiction is the high incidence to drug craving and relapse to drug-takingbehavior even after a long period of drug abstinence. In recent years, it has become clear that addictivebehaviors are paralleled by persistent alterations in the neuronal circuitry involved in motivation and rewardprocessing. For instance, it has been found that exposure to drugs of abuse leads to changes in synapsedensity and physiology in the medial prefrontal cortex (mPFC) and nucleus accumbens (NA). To date, littleis known about drug-induced synaptic plasticity events at the molecular level. Therefore, we designed astudy to examine changes in the synaptic proteome of the mPFC and NA after long-term abstinence fromheroin self-administration and after cue-conditioned reinstatement of heroin seeking behavior usingiTRAQ TM based proteomics. We found that in the mPFC and NA abstinence from heroin self-administrationleads to a persistent down-regulation of proteins that are constituents of extra-cellular nets closelysurrounding synapses. Furthermore, cue-conditioned reinstatement of heroin seeking behavior wasassociated with an increase in the expression of proteins involved in clathrin-dependent endocytosis in themPFC. In addition, we observed a down-regulation of the GluR2 isoform of the AMPA receptor, which mayindicate an increase in clathrin-mediated endocytosis of the GluR2 subunit in the mPFC after reinstatementof heroin seeking behavior. Together, these data suggest that heroin abstinence and reinstatement involvechanges in the synaptic proteome of the mPFC and NA that may underlie the persistence of relapse toheroin seeking behavior.KEY WORDS: opiates, reinstatement, proteomics, synaptic plasticity, extracellular matrixTELEPHONE-NUMBER: 020 598 7122/ 118E-MAIL-ADDRESS: mvdoever@bio.vu.nl75

TITLEBRIEF TREATMENT WITH THE GLUCOCORTICOID RECEPTOR ANTAGONIST MIFEPRISTONENORMALIZES THE CHRONIC STRESS-INDUCED REDUCTION OF ADULT HIPPOCAMPALNEUROGENESISAUTHORSCharlotte A. Oomen, Joseph L. Mayer, E. Ronald de Kloet, Marian Joëls and Paul J. LucassenDEPARTMENT/INSTITUTESILS-CNS, University of Amsterdam, AmsterdamABSTRACTDysregulation of the hypothalamo-pituitary-adrenal (HPA)-axis is common during depression. Elevatedcorticosteroid levels affect hippocampal function and structure and in rodents suppress adult neurogenesis.It is hypothesized that similar reductions in neurogenesis occur in humans, which might contribute to thehippocampal volume reductions observed in depression. Additionally, the loss of hippocampalneurogenesis in rodents nullifies the behavioral effects of current antidepressants.In support of a role for the HPA-axis in depression, recent clinical studies have shown that theglucocorticoid-receptor antagonist mifepristone relieves symptoms of psychotic depression after brieftreatment periods. To better understand its mechanism, we investigated mifepristone’s cellular effects.As mifepristone rapidly reversed reduced adult neurogenesis caused by high levels of exogenouslyadministered corticosterone (Mayer et al., JNE in press), we here tested its efficacy after chronic stress.Mifepristone rapidly reversed the chronic stress-induced reduction of adult neurogenesis, while the drugalone had no effect.These data indicate that mifepristone is particularly potent in a high corticosterone environment. Similarly toits clinical efficacy, mifepristone’s effects on adult neurogenesis are rapid and positive, and may thereforebe important for its mechanism of action.TELEPHONE NUMBER: 020-5257719E-MAIL-ADDRESS: coomen@science.uva.nl76

TITLENORMAL VALUES FOR PHENOTYPIC ABNORMALITIES IN SCHOOL CHILDRENAUTHORSHeval M. Ozgen 1 , Johannes H.M. Merks 2 , Theresa L.M. Cluitmans 3 , Jaqueline M. van der Burg-van Rijn 4 ,Jan Maarten Cobben 1 , Flora M. van Leeuwen 5 , and Raoul C.M. Hennekam 1,6DEPARTMENT/INSTITUTE1 Department of Pediatric Genetics, and 2 Department of Pediatric Oncology, Emma Children’s Hospital,Academic Medical Center, Amsterdam; 3 Department of Epidemiology, Community Health CareDepartment, Kennemerland, Haarlem; 4 Department of Youth Health Care, Community Health CareDepartment Kennemerland, Haarlem; 5 Department of Epidemiology, Netherlands Cancer Institute,Amsterdam; 6 Institute of Child Health, Great Ormond Street Hospital for Children, University CollegeLondon, London, UKABSTRACTClinical morphology has proved a strong tool in the delineation of many syndromes and a powerfulinstrument for detecting candidate genes. Only four studies were performed describing the prevalence ofphenotypic abnormalities in a control population. However, all four were performed on newborn infants.Here we report on a study of morphological characteristics in a larger group of normal school children.Children from elementary schools seemed the most accessible and unbiased group. They were examinedduring a screening examination, initiated by the community health care department in the region ofHaarlem. Also schools were visited of children that were missed at this screening. All children underwent abody surface examination performed by a medical doctor directed to phenotypic abnormalities usingdetailed definitions.From February 2004 to March 2005, 1007 children were included. Median age was 10 years (range 8 - 14yr), sex ratio was equal. 924 children were of Caucasian descent, 83 others of mixed ethnic backgrounds.Children were from rural and urban communities with equal division over socio-economic classes.Reliability was tested by independent scoring of 111 children by two observers, showing a kappa score of0.85. Normal values for a selection of widely used phenotypic abnormalities will be presented.These normal values are indispensable for validation of frequency dependent classifications of phenotypicabnormalities. Furthermore they will allow a proper judgment of patterns of phenotypic abnormalities foundin various patient groups with disorders suspected to be of developmental origin.KEY WORDS: Dysmorphology, phenotype, normal values, subgroupsTELEPHONE-NUMBER: 030-2507470E-MAIL-ADDRESS: h.m.ozgen@umcutrecht.nl77

TITLENOISE CORRELATIONS CAN HELP OR HINDER DISCRIMINATION IN V1AUTHORSJasper Poort, P.R. RoelfsemaDEPARTMENT/INSTITUTEVision and Cognition, Netherlands Institute for Neuroscience, KNAW, AmsterdamABSTRACTThe nature of the neural code is subject of an ongoing debate in neuroscience. Traditionally, information isthought to be carried in the spike rate of neurons. However, information might also be carried in thecorrelation of spike rates across multiple neurons. It is well known that the response of a neuron to thesame stimulus shows a great trial-by-trial variability. Here we look at the correlation between the spike rateof recording sites in V1 over trials. Our aim is to see whether this “noise correlation” will improve or degradediscrimination in this area.Neuronal responses in cortical area V1 were recorded while monkeys performed a curve-tracing task. Inthis task, two curves were presented of which one was connected to the fixation point (target curve) andone was not (distracter curve). The task was to indicate which of two red circles was connected to a fixationpoint by making a saccade to the end of the target curve. To solve this task, the animals had to grouptogether all contour segments that belonged to the target curve and ignore the segments that belonged tothe distracter curve. Previous work has revealed a neuronal correlate of object-based attention using thistask: neuronal responses in V1 evoked by the various segments of a target curve were enhanced relative toresponses evoked by a distracter curve. .This attentional modulation can be utilized to determine whether the target curve or the distracter curve ispresented in the receptive field (RF) of the neuron. We use signal detection theory to quantify thediscrimination performance of single sites and combinations of sites. To assess whether noise correlationsare helpful we can compare the predictions that take noise correlations into account with the predictionsthat do not. We conclude that noise correlations can improve performance in combinations of sites thathave their RF on different curves and degrade performance when sites have a RF on the same curve.KEY WORDS: Attention, discrimination, V1, correlationTELEPHONE-NUMBER: 020-5664698, 06-18144819E-MAIL-ADDRESS: j.poort@nin.knaw.nl78

TITLECORTICOSTERONE TIME-DEPENDENTLY MODULATES BETA-ADRENERGIC EFFECTS ON LTP INHIPPOCAMPAL DENTATE GYRUSAUTHORSZhenwei Pu, Harm Krugers, Marian JoëlsDEPARTMENT/INSTITUTECentre for Neuroscience, Swammerdam Institute for Life Sciences, University of AmsterdamABSTRACTExposure to stress can promptly activate the hypothalamo-pituitary-adrenal axis as well as the autonomicnervous system, resulting in elevated levels of corticosterone and noradrenaline. These substances candirectly influence brain structures that are relevant to remembering the stressful condition. Alongside theinstant modulation by noradrenaline, corticosterone can affect neural cellular functioning in different timedomains, either through its classical genomic actions or via rapid, non-genomic effects as were recentlydescribed for hippocampal CA1 long-term potentiation (LTP). Unlike the CA1 region, in vitro field potentialrecordings in the dentate gyrus showed that application of corticosterone alone could not rapidly facilitateLTP induction by a mild stimulation paradigm. Yet, facilitated induction of LTP was rapidly induced by thebeta-adrenergic agonist isoproterenol. When corticosterone was applied simultaneously with isoproterenol,a further transient enhancement of synaptic strength was seen. By contrast, pretreatment of corticosteroneseveral hours in advance to isoproterenol did not result in facilitated LTP. We here show that corticosteronecan regulate noradrenergic modulation of synaptic plasticity in a time-dependent manner. This may offerclues to how stress hormones interact with each other thus optimizing brain functionality to cope with lifethreats and to develop survival strategies.KEYWORDS: Corticosterone, noradrenaline, long term potentiation (LTP), dentate gyrus, stressTELEPHONE-NUMBER: 020-5257646E-MAIL-ADDRESS: zpu@science.uva.nl79

TITLECANNABIS USE AND GRAY MATTER VOLUME IN SCHIZOPHRENIA: A FIVE-YEAR LONGITUDINALMRI STUDYAUTHORSMonica Rais, W. Cahn, N.E.M. van Haren, H.E. Hulshoff Pol, E. Caspers, H.G. Schnack, R.S. KahnDEPARTMENT/INSTITUTERudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht,UtrechtABSTRACTBackgroundProgressive gray matter volume reductions have been found in schizophrenia and greater changes seem tobe related to poorer outcome 1,2 As patients with schizophrenia who use cannabis have a worse prognosis 3the progressive gray matter change in these patients might be even greater.MethodFifty-one patients with recent-onset schizophrenia (cannabis users n=19; non-users n=32) and thirty-onematched healthy comparison subjects were included in this five year longitudinal MRI study. All subjectswere assessed at inclusion and after five years. Total brain, gray and white matter, cerebellar, lateral andthird ventricle volumes were measured. Percentages of volume change over time were calculated.Univariate analysis of covariance and pairwise comparisons were performed.ResultsCannabis using patients, non-using patients and healthy comparison subjects differed significantly in totalbrain, gray matter, lateral and third ventricles and cerebellum volumes. No change in white matter wasobserved between the groups.Cannabis using patients with schizophrenia showed a more rapid decrease in total brain and cerebellarvolume and increase in lateral and third ventricle volumes as compared to healthy subject and non-usingpatients. Gray matter volume decrease occurred in all patients with schizophrenia as compared to healthysubjects, but was significantly greater in patients using cannabis.ConclusionIn schizophrenia progressive gray matter volume decrease occurs during the first five years of illness.Cannabis use causes an additional decrease of gray matter in patients with schizophrenia and could beexplained by either a worse illness outcome or the effects of cannabis.References:1. Cahn W, Hulshoff Pol HE, Lems EBTE, van Haren NEM, Schnack HG, van der Linden JA, SchothorstPF, van Engeland H, Kahn RS. Brain Volume Changes in First-Episode Schizophrenia: a one-year followupstudy. Archives of General Psychiatry 2002;59: 1002-1010.2. Mathalon DH, Sullivan EV, Lim KO, Pfefferbaum A. Progressive Brain Volume Changes and the ClinicalCourse ofSchizophrenia in Men: A Longitudinal Magnetic Resonance Imaging Study. Arch Gen Psychiatry.2001;58:148-157.3. Lambert M, Conus P, Lubman DI, Wade D, Yuen H, Moritz S, Naber D, McGorry PD, SchimmelmannBG. The impact of substance use disorders on clinical outcome in 643 patients with first-episode psychosis.Acta Psychiatr Scand. 2005 Aug;112(2):141-8.TELEPHONE NUMBER: 030-2509931E-MAIL-ADDRESS: mrais@umcutrecht.nl80

TITLEROLE OF β-CATENIN IN VISUAL PLASTICITYAUTHORSM. Hadi Saiepour and Christiaan N. LeveltDEPARTMENT/INSTITUTEResearch Group Molecular Visual Plasticity, Netherlands Institute for Neurosciences, KNAW, Amsterdam.ABSTRACTβ-catenin is a central component of both cadherin-catenin cell adhesion complex and the Wnt signalingpathway. Upon binding to cell surface receptors, Wnts initiate an intracellular cascade that, via severalintermediate steps, leads to translocation of β-catenin to the nucleus. There, together with transcriptionfactors of the T-cell factor/lymphoid enhancer-binding factor 1 (TCF/LEF1) family, β-catenin regulatesexpression of target genes like Ephrins which have been shown to be involved in neuronal morphogenesis.β-catenin-cadherin complex is thought to promote adhesion between pre and post synaptic elements in thebrain. This complex regulates neuronal adhesion, which leads to regulating total axonal and dendritic lengthand arborization. Inhibition of this complex causes reduction of mature spines in favor of elongated, lessefficient, spines. β-catenin seems to be an interesting candidate for regulating spine turnover and synapticplasticity.The Cre-lox recombination system is used to produce mice in which β-catenin gene is knocked out in atemporally and spatially restricted fashion. Crossing β-catenin loxP mice with a Cre expressing line, with abroad expression, causes excision of exons 2-6, thereby knocking out β-catenin gene in most pyramidalneurons of the visual cortex. These mice are used for functional studies like intrinsic optical imaging.For morphological studies, β-catenin loxP mice are crossed to a transgenic line which expresses enhancedGFP. Intracortical Cre delivery with lentivirus will cause simultaneous expression of EGFP and inactivationof β-catenin in individual neurons.KEY WORDS: β-catenin, Plasticity, enhanced GFP, Cre-lox recombinationTELEPHONE-NUMBER: 020-5664384.E-MAIL-ADDRESS: saiepour@nin.knaw.nl81

TITLEDUTCH PREDICTION OF PSYCHOSIS STUDY: PARAMETERS OF SOCIAL FUNCTIONING INADOLESCENTS AT HIGH RISK OF PSYCHOSISAUTHORSMirjam Sprong, H. Swaab, P.F. Schothorst, H. van EngelandDEPARTMENT/INSTITUTERudolf Magnus Institute of Neuroscience, Department Psychiatry, Section Neurodevelopmental Disorders,University Medical Center Utrecht, UtrechtABSTRACTIntroductionThere is a lot of evidence of social impairment in Ss suffering from psychotic disorders. This has often beenexplained by the social cognitive deficits that have been found in these Ss, in particular with regard to(facial) emotion recognition and mentalizing (or “Theory of Mind”). However, there is only limited evidenceof a relationship between measures of social cognition and social functioning. In addition, little is knownabout the timing of social cognitive deficits in the development of psychosis.MethodsMeasures of social cognition (i.e. facial recognition, facial emotion recognition and mentalizing) and socialfunctioning are assessed in two groups at high risk for psychosis: 1. Ss at ultra-high risk of psychosisdisplaying putatively prodromal symptoms (i.e. brief, limited and intermittent psychotic symptoms,attenuated positive symptoms, basic symptoms) and/or a combination of a genetic risk and decline ingeneral functioning, and 2. Ss with primarily social functioning, affect regulation and information processingimpairments (i.e. Multiple Complex Developmental Disorder), who are also considered to be at high risk forpsychosis. In addition, both high-risk groups are compared with healthy controls.ResultsPreliminary results have indicated that both high-risk groups already have social cognitive deficitscompared to normal controls. In addition, both high-risk groups did not differ significantly from one another.This suggests that social cognition is already impaired before the onset of psychosis and that this deficit istrait dependent rather than a consequence of the psychosis. In this paper, the final results and conclusionswill be presented.KEY WORDS: Social cognition, psychosis, schizophreniaTELEPHONE-NUMBER: 030-2509839E-mail-ADDRESS: M.Sprong-2@umcutrecht.nl82

TITLECONVERGENCE OF PARALLEL SENSORY INFORMATION PROCESSING ROUTES IN THE RATPARAHIPPOCAMPAL REGIONAUTHORSNiels M. van Strien, S. Avci, J. Wijntjes, L. Baks-te-Bulte, A. Boekel-Boeve, M.P. WitterDEPARTMENT/INSTITUTEVU University medical center, Department of Anatomy and Neurosciences, AmsterdamABSTRACTIt has been proposed that separate information processing pathways exist which connect the neocortexwith the hippocampus. Current belief is that the divergent information that is transmitted along thesepathways is associated in the hippocampus. However, this association might also occur earlier in theparahippocampal-hippocampal system. Electrophysiological studies in the rat and in the monkey point tothe entorhinal cortex and specific parts of the perirhinal and postrhinal cortices as likely sites forconvergence. To test this we injected different anterograde tracers in the perirhinal and postrhinal cortices.Preliminary results show overlap of labeled projections, originating from perirhinal and postrhinal neurons,in the entorhinal cortex. This strongly supports the likelihood of convergence in the entorhinal cortex, but isnot definite proof. Therefore, in ongoing experiments, we inject a third, retrograde tracer in the dorsalhippocampus, to examine if convergence occurs on entorhinal neurons that project to the hippocampus(see Figure 1). Further analysis will involve intracellular filling of identified projection-neurons to visualizetheir complete dendritic tree, to establish if convergence actually occurs at the single cell level.Figure 1. Injection sites of tracers and possible location of convergence.Abbreviations: PER: perirhinal cortex; POR: postrhinal cortex; LEA: lateral entorhinal cortex; MEA: medialentorhinal cortex; FG: fluorogold; BDA: biotinylated dextran-amine; PHA-L: phaseolus vulgarisleucoagglutinin.KEY WORDS: Memory, anatomy, parahippocampal region, entorhinal cortex, perirhinal cortex, postrhinalcortex, tracing, connectivityTELEPHONE-NUMBER: 020-444804783

TITLEA PARAMETRIC EVALUATION OF MODELS TO MEASURE THE MOTIVATIONAL PROPERTIES OFCOCAINE IN RATSAUTHORSMaartje M.J. Veeneman, M. van Ast and L.J.M.J. VanderschurenDEPARTMENT/INSTITUTERudolf Magnus Institute of Neuroscience, Dept. of Pharmacology and Anatomy, University Medical CenterUtrecht, UtrechtABSTRACTDrug addiction is a major problem in Western society today. During the development of addiction, casualdrug use escalates so that ultimately, control over drug use is persistently lost. In the present project, weaim to investigate whether a prolonged history of drug taking changes the motivational aspects and theneural substrates involved in intravenous cocaine self-administration. As a first step, two variants of theseeking-taking chain (ST) schedule of reinforcement were evaluated. In the ST schedule, rats have torespond on one lever (‘seeking lever’) to gain access to a second lever (‘taking lever’), responding on whichproduces an intravenous infusion of cocaine. The advantage of the ST schedule above other schedulesoften used in addiction research, is that this schedule explicitly distinguishes between the acts of drugseeking and drug taking, thus giving animals control over their actual drug consumption. In the first variantof the ST schedule, rats were required to respond on the seeking lever under a random time interval (ST-RI). In the second version, responding on the seeking lever occurred under a progressive ratio schedule(ST-PR), meaning that the response requirement on the seeking lever increased after every earnedcocaine infusion. In both schedules we tested the effects of different drug unit doses, treatment with adopamine receptor antagonist and extinction.Under the ST-RI schedule, the motivational value of a reinforcer is measured by determining the rate ofresponding on the seeking lever. Remarkably, we observed no difference in presses per minute whenanimals responded for different unit doses of cocaine. Treatment with a dopamine receptor antagonist dosedependently decreased response rates and during extinction, response rates gradually decreased oversessions. Under the ST-PR schedule, motivation for a given reinforcer is expressed as the breakpoint,which is the maximum number of lever presses an animal is prepared to perform for one single reward. Weobserved a dose-dependent increase in breakpoints with increasing unit doses of cocaine, indicating thatthe rats were more motivated work for a larger reward. Furthermore, response rates decreased dosedependently when animals were treated with a dopamine receptor antagonist and during extinction weobserved an abrupt decrease in breakpoints. Thus, responding under a seeking-taking paradigm with aprogressive ratio schedule of reinforcement is more sensitive to measure differences in motivation forcocaine than responding under a seeking-taking paradigm with a random interval schedule.KEY WORDS: Addiction, seeking-taking chain schedule, motivation, rewardTELEPHONE-NUMBER: 030-2538845E-MAIL-ADDRESS: m.m.j.veeneman@med.uu.nl84

TITLEA MODEL FOR SPECIFIC DE- AND REMYELINATION IN RODENT WHOLE BRAIN SPHEROIDCULTURESAUTHORSElly J.F. Vereyken, C.D. Dijkstra, C.E. TeunissenDEPARTMENT/INSTITUTEDepartment of Molecular Cell Biology and Immunology, VUmc Medical Center, AmsterdamABSTRACTThe model most often used to study demyelination occurring in MS is the experimental autoimmuneencephalitis (EAE) model. During EAE, demyelination is induced by an autoimmune reaction, while in MSoligodendrocyte damage is probably causal to the autoimmune reaction taking place. This difference is avery important disadvantage of the EAE model. Furthermore, EAE often involves large numbers of animals.The aim of this study is to develop a specific in vitro demyelination model using whole brain spheroidcultures. The neuronal and glial cell types present in this model form three-dimensional contacts, leading tomyelinated axons.Methods: Using the spheroid culture system we investigated the characteristics of demyelination based onrepeated exposure to lysolecithin (LPC). LPC and various drugs were added 3 times a week in differentconcentrations. After one week of treatment medium was replaced and the spheroids were left to recoverfor a week.Results: Decreased myelin basic protein (MBP) staining and 2’,3’, cyclic nucleotide 3’-phosphodiesterase(CNPase) activity were observed after one week. Preliminary results indicate that remyelination can takeplace, since after a week recovery MBP staining was observed. Specificity of the treatment foroligodendrocytes was confirmed by immunostaining and concentration measurements of astrocyte,microglia and neuronal markers. We studied the mechanism of demyelination induced by LPC, e.g. the roleof oxygen radicals or membrane cholesterol contents. Both MBP staining and CNP-ase activity wasrecovered when spheroids were treated with vitamin E and LPC together compared to LPC alone.Lovastatin and simavastatin did not protect against the demyelination induced by LPC.Conclusions: LPC probably induces ROS generation in oligodendrocytes and thereby demyelination,explaining the protective effect of vitamin E. Changes in membrane cholesterol contents and thereforefluidity might not be a factor in LPC-induced demyelination, since statins did not have any effect. Thespecific demyelination observed in this in vitro model supports the use of this model in research into themechanisms of de- and remyelination in MS. Further, the model can be used in preclinical drug or celltransplant testing, reducing the number and discomfort of animals.KEY WORDS: Multiple Sclerosis, demyelination, remyelination, whole-brain spheroid culture, lysolecithinand vitamin ETELEPHONE-NUMBER: 020-4448083E-MAIL-ADDRESS: ejf.vereyken@vumc.nl85

TITLEINVOLVEMENT OF DOPAMINE METABOLISM IN RATS EXPOSED TO ACTIVITY-BASED ANOREXIAAUTHORSLinda A.W. Verhagen, J.J.G. Hillebrand, C.E. de Rijke CE, R.A.H. AdanDEPATRMENT/INSTITUTERudolf Magnus Institute of Neuroscience, Department of Pharmacology & Anatomy, University MedicalCenter UtrechtABSTRACTAnorexia nervosa (AN) is a severe psychiatric disorder characterized by suppressed food intake andexcessive physical activity. Of all psychiatric disorders, AN has the highest mortality rate. Recently in ourlab, it has been shown that AN patients and rats treated with Olanzapine, an atypical antipsychotic withhigh affinity for serotonin and dopamine receptors, display reduced physical activity and have increasedbody weight.In present study, we determined alterations in key enzyme activity of dopamine metabolism during AN. Tostudy AN, we used the rat model called activity-based anorexia (ABA). In this ABA model, food availabilityis restricted to a daily 1-h period and the animals are allowed voluntary exercise in a running wheel. Thisresults in increased physical activity, decrease in food intake and body weight loss. Female rats wereexposed to ABA until they reached a relative body weight of 75% and were then sacrificed. mRNAexpression levels of tyrosine hydroxylase (dopamine synthesizing enzyme) in the ventral tegmental areawere analyzed using quantitative real-time PCR on punches of brain nuclei. Our results suggest thatincreased activation of the dopaminergic system correlates with the hyperactivity in ABA.KEY WORDS: Anorexia nervosa, hyperactivity, dopamineTELEPHONE-NUMBER: 030 2533113E-MAIL-ADDRESS: L.a.w.verhagen@med.uu.nl86

TITLECHOLINERGIC AND DOPAMINERGIC INTERACTION AT THE CORTICOSTRIATAL SYNAPSE INPARKINSON’S DISEASEAUTHORElizabeth WansinkDEPARTMENT/INSTITUTECentre for Neurogenomics and Cognitive Research, Section Experimental Neurophysiology, VrijeUniversiteit AmsterdamABSTRACTParkinson’s disease (PD) is one of the most common degenerative neurological diseases. This disorder ischaracterized by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), part of thebasal ganglia. Activity-dependent changes in efficacy of glutamatergic corticostriatal synapses are crucialfor information and learning processes that are dependent on the Basal Ganglia. Corticostriatal synapticplasticity depends on dopamine and acetylcholine (ACh) receptor activation and in rodent models of PD it isstrongly reduced. Little is known about the role of different types of AChRs in corticostriatal synapticplasticity. To compensate for the loss of striatal DA receptor stimulation in PD, increased levels of corticalsynchrony through striatal or cortical AChR stimulation could improve conditions for corticostriatal synapticplasticity in PD.The first aim of this project is to study the interaction between ACh and DA in spike-timing-dependentplasticity in corticostriatal synapses, and to investigate whether AChR stimulation can restore corticostriatalsynaptic plasticity in striatal dopamine depletion and mouse models of PD (DJ-1 knockout). In addition, wewill examine whether AChR activation will ameliorate parkinsonian-like cognitive and motor symptoms inthese animals.The results of this research will provide clues whether cholinergic receptor stimulation is useful as apotential target in therapy for PD patients.KEY WORDS: Parkinson’s disease, corticostriatal synaptic plasticity, DJ-1 knockoutTELEPHONE-NUMBER: 020-5987032E-MAIL-ADDRESS: elizabeth@cncr.vu.nl87

TITLEEVENT-RELATED POTENTIALS AND SECONDARY TASK REFORMANCE DURING SIMULATEDDRIVINGAUTHORSAnnelies E. Wester, K.B.E. Böcker, E.R. Volkerts, J.C. Verster, J.L. KenemansDEPARTMENT/INSTITUTEUtrecht Institute for Pharmaceutical Sciences, Department of Psychopharmacology, Utrecht UniversityABSTRACTIntroductionInattention and distractibility account for a substantial number of traffic accidents. In the present studyattentional capacity and distractibility were studied by recording event-related potentials (ERPs) to auditoryoddball-stimuli during a steering simulator test in healthy volunteers.MethodsTwenty healthy participants performed two 20-minute drives in the Divided Attention Steering Simulator(DASS). Participants were instructed to keep the vehicle in the centre of the road that was depicted on thecomputer screen. Primary outcome measure was the standard deviation of lateral position, relative to thecentre of the road (steering error). To examine the impact of secondary task performance on drivingperformance, an active (n=10) or passive (n=10) auditory novelty-oddball paradigm was presented duringthe steering simulation test. The novelty-oddball paradigm consisted of 80 % standard tones, 10 % devianttarget tones and 10 % novel environmental sounds. In addition to reaction times to the presented stimuli,ERP components were recorded to the oddball stimuli. ERPs of interest were the P3a, which is typicallyelicited by task-irrelevant novel stimuli and reflects involuntary switching of attention, and the P3b, which istypically elicited by task-relevant stimuli and reflects the degree of attentional capacity. Simulated drivingwith and without performing the secondary task was compared. In addition, secondary task performancewas assessed before and after the driving test.ResultsSimulated driving performance was not affected by performing the secondary oddball task (F=0.82,p=.376). Reaction times on the secondary task while driving did not differ significantly from those measuredwhen the secondary test was performed alone, before or after the simulator test (F=3.23, p=.100).However, P3a amplitude to secondary task performance was significantly reduced in dual-task conditionsduring the passive oddball task (F=32.12, p

TITLEEFFECTS OF NMDA RECEPTOR ACTIVITY ON IN VIVO FIRING PATTERNS OF SINGLE UNITS INORBITOFRONTAL CORTEX OF AWAKE MALE WISTAR RATSAUTHORSE.J. Marijn van Wingerden 1 , Ruud N.M.J.A. Joosten 1,2 , Matthijs G.P. Feenstra 2 , Cyriel M.A. Pennartz 1DEPARTMENT/INSTITUTE1 Animal Physiology & Cognitive Neuroscience, SILS Centre for Neuroscience (CNS), University ofAmsterdam (UvA), 2 Netherlands Institute for Neuroscience, AmsterdamABSTRACTThe orbitofrontal cortex (OFC) is thought to guide behaviour on the basis of the value of predictedreinforcers. There is evidence to suggest that firing patterns of OFC neurons reflect the value of a stimuluspredicting reward. However, the transmitter mechanisms underlying the formation of these predictive firingpatterns remain unknown. One possible candidate is the glutamatergic neurotransmission system.We recorded activity from OFC neurons in 2 awake male Wistar rats in a familiar environment using anelectrode array holding 14 independently moveable tetrodes. Additionally, we modified this ‘hyperdrive’ toaccommodate a microdialysis probe. Used in reversed operation mode, we unilaterally perfused the OFCduring recordings with 1) a 0.5 mM solution of the selective NMDA-R agonist NMDA, 2) a 0.5 mM solutionof the competitive NMDA-R antagonist D-APV, or 3) a 2% lidocaïne solution blocking spike generation,allowing us to assess the dynamics of drug application, and 4) an aCSF control solution. Recovery of theprobe membrane was estimated at 10-15% by HPLC analysis.A total of 67 cells was recorded in 4 sessions. Of these, 58 cells exhibited stationary firing patterns duringthe course of the session and thus could be considered for analysis. To assess the effect of the differentsolutions on single unit firing, we calculated mean firing rates over 30 second bins during perfusion intervalsfor each cell. Compared to aCSF perfusions, the perfusion of 0.5 mM NMDA induced a cessation of firing in96% of neurons. Perfusion of 2% lidocaïne blocked firing activity in 83% of cells. Finally, perfusion of 0.5mM D-APV did not markedly modulate firing rates in any of the recorded cells.These findings confirm that the modified hyperdrive, or ‘combidrive’, can be used for time-specific localapplication of drugs during extracellular recordings in awake rats. Whereas the cessation of firing inducedby NMDA can be explained by a depolarizing block of susceptible cells, the lack of D-APV suggests that invivo NMDA receptors do not strongly contribute to baseline firing of cells.KEY WORDS: Orbitofrontal cortex, ensemble recordings, microdialysis, NMDA(-receptor), AP-VTELEPHONE-NUMBER: 020-5257713E-MAIL-ADDRESS: e.j.m.vanwingerden@uva.nl89

TITLEQUANTIFICATION OF DOPAMINE TRANSPORTER BINDING USING [ 18 F]FP-β-CIT AND POSITRONEMISSION TOMOGRAPHYAUTHORSMaqsood Yaqub, R. Boellaard, B.N.M. van Berckel, M.M. Ponsen, M. Lubberink, A.D. Windhorst,H.W. Berendse, A.A. LammertsmaDEPARTMENT/INSTITUTEDept. of Nuclear Medicine and PET Research, VU University Medical Centre, AmsterdamABSTRACTIntroductionThe dopamine reuptake transporter (DAT) is an accepted target for assessing the integrity of dopaminergicneurons. Despite the quantitative potential of PET, to date studies with the DAT ligand [ 18 F]FP- β-CIT haveonly been analysed using simple radioactivity ratios at a fixed time after bolus injection. For monitoringprogression of disease and/or impact of therapeutic interventions, however, accurate quantification ofbinding is required. The purpose of the present study was to compare different quantitative methods foranalysing human [ 18 F]FP-β-CIT studies. To this end both simulations and clinical evaluations wereperformed.MethodsDifferent kinetic (Gunn RN et al, J. of Cereb. Blood Flow and Metab., 2001, 21, 635-652) and semiquantitativemethods (often used in clinical studies) were assessed: plasma input models, simplified(SRTM) and full (FRTM) reference tissue models, standard uptake values (SUV) and SUV ratios (SUVr).Both simulations and clinical evaluations were performed to determine the effects of noise, scan durationand blood volume on Akaike model selection (Akaike H, Annals of the Institute of Statistical Mathematics,1969, 21, 243-247), and precision and accuracy of estimated parameters.Results: For noise levels seen in human studies (coefficient of variation ~ 2.5%) and typical scan durations(< 90 min), simulations provided poor fits for reversible models, both in terms of Akaike criterion, andprecision and accuracy of fitted parameters. In addition, the number of outliers was relatively highcompared with that obtained with the two-tissue irreversible model. The results for the two tissue reversiblemodel improved for longer scan durations (>120 min). Reference tissue models provided more reliable fits,which were nearly independent of noise and scan duration. Although BP estimates from reference tissuemodels showed bias (~20%), even at Vb = 0, this bias was almost constant at various noise levels. Inaddition, standard errors of the estimates obtained with SRTM were the lowest of all methods tested.For clinical data, two tissue irreversible and reversible models fitted striatum curves equally well (Akaikecriterion). However, BP from plasma input models was less precise and there were more outliers (28%-47%of striatum fits) than for BP obtained with SRTM or FRTM (~7.5% of striatum fits). Amongst all methodstested, SRTM provided the best discrimination between patients (BP~2.5) and controls (BP~5). Fordifferentiation between patients and controls, performance of SUVr was almost the same as that of SRTM,but contrast between striatum and background was lower (~30% vs 5% background for SUVr and SRTM,respectively).ConclusionIn conclusion, SRTM provided BP estimates with the highest precision and accuracy. Moreover, SRTMdiscriminated best between patients and controls, and showed the highest contrast between striatum andbackground. SRTM is therefore the method of choice for quantification of clinical [ 18 F]FP- β-CIT studies. Fordiagnostic purposes only, SUVr might be an acceptable alternative.KEY WORDS: [ 18 F]FP- β-CIT, PET, tracer kinetic model, SUV, reference tissue model, plasma input modelTELEPHONE NUMBER: 020- 4444366E-MAIL-ADDRESS: maqsood.yaqub@vumc.nl90

TITLEUNRAVELING THE INTRACELLULAR SIGNAL TRANSDUCTION MECHANISMS THAT UNDERLIEAXON GUIDANCE: MICALS LEAD THE WAYAUTHORSYeping Zhou, Dianne van den Heuvel, Youri Adolfs and R. Jeroen PasterkampDEPARTMENT/INSTITUTEDepartment of Pharmacology and Anatomy, Rudolf Magnus Institude of Neuroscience, UMC Utrecht,UtrechtABSTRACTThe proper functioning of our nervous system relies on the establishment of precise neuronal circuits.These circuits form during embryonic development when growing axons are guided to their appropriatetargets by molecular guidance cues in the extracellular environment. Axon guidance cues inducemorphological changes of the axonal growth cone through the (in)activation of a series of intracellularsignaling molecules thereby defining axon growth and guidance. However, the precise intraneuronal signaltransduction mechanisms that underlie axon guidance remain largely unknown. To better comprehendthese mechanisms we study a large family of axon guidance molecules, the semaphorins. Manysemaphorins can induce growth cone collapse and are required in vivo for the formation of neuronalconnections. We recently identified a novel family of intracellular molecules called MICALs that is essentialfor mediating the growth cone collapsing effects of semaphorins. In Drosophila, MICAL binds thesemaphorin receptor plexinA and is required for growth cone collapse induced by semaphorin. In vertebratespecies such as mice and human, three MICAL proteins have been identified (MICAL-1, MICAL-2 andMICAL-3). In our present study, we plan to examine the biochemical interaction between vertebrate plexinsand MICALs and analyze the role of MICAL proteins in axon guidance in vivo by using geneticallymanipulated mice. In addition, we will identify and characterize proteins that bind MICAL proteins to furtherunravel the intracellular signal transduction pathway down stream of semaphorins.KEY WORDS: MICAL, axon guidance, semaphorin, plexinTELEPHONE-NUMBER: 030-2533634E-MAIL-ADDRESS: yeping11@yahoo.com91

LIST OF PARTICIPANTS93

NAME SCHOOL E-MAIL-ADDRESS TEL.NR. ABS.Aerde, Karlijn van ONWA karlijn@cncr.vu.nl 020-5987099 p. 24Altena, Ellemarije ONWA e.altena@vumc.nl 020-4440685 p. 43Aukes, Maartje RMI m.aukes@umcutrecht.nl 030-2501783 p. 39Baarendse, Petra ONWA petra@cncr.vu.nl 020-5987089 n.a.Backer, Marijke de RMI marijke@mmolenaar.demon.nl 06-28685941 p. 44Berge, Simone van den ONWA s.van.den.berge@nin.knaw.nl 06-18173948 n.a.Betsalel, Ofir ONWA o.betsalel@vumc.nl 020-4442418 n.a.Bijlsma, Liesbeth RMI e.y.bijlsma@pharm.uu.nl 030-2537382 n.a.Boer, Karin ONWA karin.boer@amc.uva.nl 020-5664369 p. 45Boer, Marieke de ONWA marieke.deboer@vumc.nl 020-4448047 p. 46Boesveldt, Sanne ONWA s.boesveldt@vumc.nl 020-4440708 p. 47Boonstra, Geartsje RMI g.boonstra@psych.azu.nl 030-2507121 p. 48Boos, Heleen RMI hbm_boos@yahoo.com 030-2509931 p. 37Bossers, Koen ONWA k.bossers@nih.knaw.nl 020-5665512 p. 42Brans, Rachel RMI rbrans@azu.nl 030-2508352 p. 38Bremer, Hendrik RMI h.g.bremer@umcutrecht.nl 030-2501644 n.a.Breuer, Meg RMI m.e.breuer@pharm.uu.nl 030-2537387 p. 49Broeke, Jurjen ONWA jurjen@cncr.vu.nl 020-5986929 p. 50Buiter, Hans ONWA hbuiter@rnc.vu.nl 020-4445698 n.a.Camargo, Nutabi ONWA nutabicamargo@yahoo.fr n.a.Canto, Cathrin ONWA cb.canto@vumc.nl 020-4448049 p. 51Chafekar, Sidhartha ONWA s.m.chafekar@amc.uva.nl 020-5664959 p. 41Couey, Jay ONWA jonathan.couey@falw.vu.nl 020-5987099 n.a.Counotte, Daniëlle ONWA danielle.counotte@falw.vu.nl 020-5987122 p. 52Dekker, Nienke ONWA nienke.dekker@amc.uva.nl 020-5666289 p. 53Doorn, Ruben van ONWA r.vandoorn@vumc.nl n.a.Dudok, Jeroen ONWA jeroen@cncr.vu.nl 020-5986931 p. 54Galen, Elly van ONWA e.van.galen@nih.knaw.nl 020-5668967 p. 55Gemert, Neeltje van ONWA nvgemert@science.uva.nl 020 5257719 p. 22Gillis, Judtih ONWA j.m.gillis@amc.uva.nl 020-5664974 p. 56Grootheest, Daniël van ONWA ds.van.grootheest@psy.vu.nl 020-5988743 p. 57Heistek, Tim ONWA tim.heistek@falw.vu.nl 020-598032 p. 35Hel, Saskia van der RMI w.s.vanderhel@med.uu.nl 030-2538329 p. 58Hessel, Ellen RMI e.v.s.hessel@med.uu.nl 030-2538845 p. 59Hoekstra, Carlijn RMI c.e.l.hoekstra@umcutrecht.nl 030-2501644 n.a.Huijbers, Willem ONWA whuijber@science.uva.nl 020-5257728 n.a.Kan, Anne RMI anne_kan@hotmail.com 06-45614735 n.a.Katerberg, Hilga ONWA h.katerberg@vumc.nl 020-5989965 p. 60Koning, Jeroen RMI jpf.koning@symfora.nl 06-47692732 p. 61Kooij, Gijs ONWA g.kooij@vumc.nl 020-4448059 p. 62Koolschijn, Cédric RMI p.c.m.p.koolschijn@psych.azu.nl 030-2506032 p. 63Kooten, Imke van RMI imke.vankooten@np.unimaas.nl 043-3881034 p. 64Korecka, Joanna ONWA j.a.korecka@students.uu.nl 020-5665500 n.a.Krol, Hilde ONWA h.a.krol@amc.uva.nl 020-5664974 n.a.94

NAME SCHOOL E-MAIL-ADDRESS TEL.NR. ABS.Langen, Marieke RMI mlangen@umcutrecht.nl 030-2507084 p. 65Lee, Eunjeong ONWA elee@science.uva.nl 020-5257674 p. 66Leenaars, Cathalijn ONWA c.leenaars@nin.knaw.nl 020-5665488 n.a.Leliefeld, Paul RMI p.h.leliefeld@umcutrecht.nl 06-24884706 n.a.Loos, Maarten ONWA maarten.loos@falw.vu.nl 020-5989281 p. 33Mac Gillavry, Harold ONWA harold.macgillavry@falw.vu.nl 020-5987122 p. 67Magnée, Maurice RMI m.j.c.m.magnee@umuctrecht.nl 030-2506026 p. 68Malkki, Hemi ONWA malkki@science.uva.nl 020-2527226 n.a.Meekes, Joost RMI j.meekes@umcutrecht.nl 06-16504531 p. 69Meer, Maurits van RMI maurits@invivonmr.uu.nl 030-2535515 n.a.Mertz, Marjolijn ONWA marjolijnmertz@yahoo.co.uk n.a.Middeldorp, Jinte ONWA j.middeldorp@nih.knaw.nl 020-5665515 p. 70Min, Rogier ONWA rogier.min@cncr.vu.nl 020-5987043 p. 23Mooij, Annetrude de RMI j.g.demooij-vanmalsen@med.uu.nl 030-2538845 p. 71Møst, Els ONWA e.most@nih.knaw.nl 020-5665488 p. 72Mourik, Jurgen ONWA j.mourik@vumc.nl 020-4441770 n.a.Mulder, Martijn RMI m.mulder-7@umcutrecht.nl 030-2509840 p. 73Nederveen, Hilde RMI h.nederveen@umcutrecht.nl 030-2509840 p. 74Oever, Michel van den ONWA mvdoever@bio.vu.nl 020-5987122 p. 75Oomen, Charlotte ONWA coomen@science.uva.nl 020-5257719 p. 76Ozgen, Heval RMI h.m.ozgen@umcutrecht.nl 030-2596362 p. 77Peper, Jisca RMI j.s.peper@umcutrecht.nl 030-2507549 p. 20Poort, Jasper ONWA j.poort@nin.knaw.nl 020-5664698 p. 78Pu, Zhenwei ONWA zpu@science.uva.nl 020-5257646 p. 79Rais, Monica RMI mrais@azu.nl 030-2509994 p. 80Ramaglia, Valeria ONWA v.ramaglia@amc.uva.nl 020-5664965 p. 28Rao, Priyanka ONWA kpriyankar@gmail.com 06-27450130 n.a.Remmers, Floor ONWA f.remmers@vumc.nl 020-4443810 p. 30Ridder, Margreet ONWA mc.ridder@vumc.nl 06-41829963 n.a.Rigter, Laura ONWA lrigter@science.uva.nl 020-5257705 n.a.Roet, Kasper ONWA k.roet@nin.knaw.nl 020-5665500 n.a.Romeijn, Nico ONWA nromeijn@gmail.com 020-5665537 n.a.Rooy, Ingrid van RMI i.vanrooy-2@umuctrecht.nl 06-47416933 n.a.Saavedra, Jose ONWA jtsaavedra@amc.uva.nl 030-2965452 p. 29Saiepour, Hadi ONWA saiepour@ioi.knaw.nl 020-5664384 p. 81Sanz Sanz, Alicia ONWA a.sanz@nin.knaw.nl 020-5664687 n.a.Schagen, Sebastian ONWA s.schagen@vumc.nl 020-4441035 n.a.Sommeijer, Jean-Pierre ONWA j.sommeijer@nin.knaw.nl 06-14436479 n.a.Sprong, Mirjam RMI m.sprong-2@umcutrecht.nl 030-2509839 p. 82Sta, Marleen ONWA m.sta@amc.uva.nl 020-5664965 n.a.Stanisor, Liviu ONWA l.stanisor@ioi.knaw.nl 020-5664799 p. 25Strien, Niels van ONWA n.vanstrien@vumc.nl 020-4448047 p. 83Stronks, Christiaan RMI c.stronks@umcutrecht.nl 030-2507581 n.a.Tannemaat, Martijn ONWA m.tannemaat@nih.knaw.nl 020-5667130 p. 27Vandenbroucke, Myriam RMI m.w.g.vandenbroucke@uva.nl 020-5256741 p. 2195

NAME SCHOOL E-MAIL-ADDRESS TEL.NR. ABS.Veeneman, Maartje RMI m.m.j.veeneman@med.uu.nl 030-2538845 p. 84Velden, Floris van ONWA f.vVelden@vumc.nl 020-4441770 n.a.Vereyken, Elly ONWA ejf.vereyken@vumc.nl 020-4448083 p. 85Verhagen, Linda RMI l.a.w.verhagen@med.uu.nl 030-2533113 p. 86Verhave, Nelleke ONWA nelleke.verhave@tno.nl 015-2843047 n.a.Verlaan, Mariska RMI m.verlaan@vet.uu.nl 030-2534149 n.a.Visser, Leonie de RMI l.devisser@vet.uu.nl 030-2531232 p. 32Vliet, Erwin van ONWA vliet@science.uva.nl 020-5257893 p. 36Vo, Tam ONWA t.vo@nih.knaw.nl 020-5665500 p. 26Wansink, Elizabeth ONWA elizabeth@cncr.vu.nl 020-5987032 p. 87Wester, Annelies RMI a.e.wester@pharm.uu.nl 030-2537768 p. 88Wiegert, Olof ONWA owiegert@science.uva.nl 020-5257661 p. 34Wijntjes, Juerd ONWA j.wijntjes@gmail.com n.a.Willeboer, Krista RMI k.willeboer@umcutrecht.nl 030-2507725 p. 31Wingerden, Marijn van ONWA e.j.m.vanwingerden@science.uva.nl 020-5257713 p. 89Wolfensberger, Saskia ONWA spa.wolfensberger@vumc.nl 020-4441728 p. 19Wouda, Jelte ONWA j.wouda@vumc.nl 020-4448089 n.a.Wouters, Femke ONWA f.wouters@vumc.nl 020-4441035 n.a.Yakub, Maqsood ONWA maqsood.yaqub@vumc.nl 020-4444608 p. 90Zanten, Jeroen van ONWA jeroenza@ggzba.nl 020-7884522 n.a.Zeeuw, Patrick de RMI patrickdz@zonnet.nl 020-2507084 n.a.Zhou, Yeping RMI yeping11@yahoo.com 030-2533634 p. 91Ziermans, Tim RMI t.ziermans@umcutrecht.nl 030-2503275 n.a.Zijlstra, Fleur ONWA c.zijlstra@amc.uva.nl 020-5664309 p. 18Zinkstok, Janneke ONWA j.r.zinkstok@amc.uva.nl 020-5662001 p. 40staffBär, Dop RMI p.r.bar@umcutrecht.nl 030-2507296Burnashev, Nail ONWA nail.burnashev@falw.vu.nl 020-5986986Haren, Neeltje van RMI n.haren@azu.nl 030-2507130Hol, Elly ONWA e.hol@nih.knaw.nl 020-5665503Hulshoff Pol, Hilleke RMI hhulshof@umcu.nl 030-2506019Kas, Martien RMI m.j.h.kas@med.uu.nlchristiaan.dekock@mpimfheidelberg.mpg.deKock, Christiaan deLevelt, Christiaan ONWA c.levelt@ioi.knaw.nl 020-5665359Lucassen, Paul ONWA lucassen@science/uva.nlSakmann, Bert zpsecr@mpimf-heidelberg.mpg.de p. 17Verhaagen, Joost ONWA j.verhaagen@nin.knaw.nlVerhage, Matthijs ONWA matthijs@cncr.vu.nl 020-4446936Witter, Menno ONWA mp.witter@vumc.nl 020-444804896

Karlijn van AerdeExperimental NeurophysiologyFALW - VUDe Boelelaan 10851081 HV AMSTERDAMEllemarije AltenaNetherlands Institute for NeuroscienceMeibergdreef 471105 BA AMSTERDAM-ZOMaartje AukesPsychiatryUMCUHeidelberglaan 1003584 CX UTRECHTPetra BaarendseFunctional GenomicsVUmcDe Boelelaan 10851081 HV AMSTERDAMMarijke de BackerPharmacology and AnatomyRMIUniversiteitsweg 100 str. 4.3163584 CG UTRECHTDop BärGraduate School Biomedical SciencesHvdB gebouw HB405cP.O. Box 855003508 GA UTRECHTSimone van den BergeCellular Quality ControlNetherlands Institute for NeuroscienceMeibergdreef 471105 BA AMSTERDAM-ZOOfir BetsalelMetabolic UnitVUmcDe Boelelaan 11171081 HV AMSTERDAMLiesbeth BijlsmaPsychopharmacologyUIPS/Rudolf MagnusSorbonnelaan 163584 CA UTRECHTKarin Boer(Neuro)pathologyAcademisch Medisch CentrumMeibergdreef 91105 AZ AMSTERDAMMarieke de BoerAnatomy and NeurosciencesVrije Universiteit Medisch CentrumVan der Boechorststraat 71007 MB AMSTERDAMSanne BoesveldtNeurology - rec. JVUmcP.O. Box 70571007 MB AMSTERDAMGeartsje BoonstraAdult Psychiatry, division BrainUMCUHeidelberglaan 1003584 CX UTRECHTHeleen BoosPsychiatryUMCUHeidelberglaan 1003584 CX UTRECHTKoen BossersNetherlands Institute for NeuroscienceMeibergdreef 471105 BA AMSTERDAM-ZORachel BransPsychiatryRudolf Magnus Institute of NeurosciencesHeidelberglaan 1003584 CX UTRECHTHendrik BremerOtorhinolargyngologyUMCUHeidelberglaan 1003584 CX UTRECHTMeg BreuerPsychopharmacologyUIPS/ Rudolph MagnusSorbonnelaan 163584 CA UTRECHTJurjen BroekeFunctional GenomicsCNCRDe Boelelaan 10851081 HV AMSTERDAMHans BuiterNuclear Medicine & PET ResearchICENDe Boelelaan 1085c1081 HV AMSTERDAM97

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