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3.11 Dynamic integration of subplate neurons into the barrel cortex during postnatal development in the Golli-tau-eGFP (GTE) mouse Jethwa A, Piñon MC, Jacobs E, Campagnoni A, Molnár Z Dept Physiology, Anatomy & Genetics, Oxford University and Semel Institute for Neuroscience & Human Behaviour, UCLA, California. Understanding the early steps of cortical development requires knowledge of the largely transient population of subplate neurons (SPn). Much of the information about the role of SPn in thalamocortical patterning is derived from SP specific ablation studies in the visual cortex of carnivores (Ghosh and Shatz, 1992). The Gollitau-eGFP transgenic mouse, where the reporter gene expression is largely confined to layer VIb allows visualisation of SPn and their projections (Jacobs et al., 2007). In this study we describe the dynamic integration of SPn into the barrel cortex at postnatal (P) ages P0-P14. Subplate projections innervate layer IV in the overlying cortex. The patterning of these projections to the primary somatosensory cortex (S1) was visualized by fluorescent optical imaging of the GFP in coronal and tangential sections. GFP labelled cells initially project diffusely into layer IV of the cortex, then by P6 to the barrel hollow. By P10-14 this pattern gradually changes so that the projections are predominantly in the barrel septa. To determine whether this intracortical reorganisation is dependent on peripheral pattern, whiskers of row A were removed at P0 and the subplate projections to S1 were examined at P10. In the contralateral region corresponding to row A, bisbenzimide counterstain revealed the lack of septa and GFP distribution the lack of clustering of subplate projections. Our findings suggest a dynamic integration of SPn within the barrel cortex which is at least partly dependent on the sensory periphery. 3.12 Role of FMRP and mGluR5 in the developing mouse primary somatosensory cortex Wijetunge L S, Till S M, Dolen G, Gillingwater T H, Bear M F, Kind P C Authors 1,2,4 & 6, University of Edinburgh, Hugh Robson Building, Edinburgh, EH8 9XD, UK, , Authors 3 & 5, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 46-3301, Cambridge, MA, 02139, USA Fragile X syndrome (FXS) is the most common genetically inherited form of mental retardation and results from the loss of the fragile X mental retardation protein (FMRP). The mGluR theory of FXS postulates that FMRP limits group 1 mGluR signalling and the exaggerated signalling of mGluRs underlies some aspects of the FXS pathology (Bear et al., 2004). We have previously shown that mGluR5-/- mice fail to form “barrels”, the characteristic cytoarchitectural units found in layer 4 of the primary somatosensory cortex (S1; Hannan et al., 2001). We now show that FMRP also regulates barrel development; Fmr1-/- mice show a significant decrease in barrel segregation compared to WT mice. To gain insight into the cellular mechanisms regulated by FMRP, we examined its spatiotemporal expression profile during barrel formation. FMRP was present in cell soma of all cortical layers at all ages examined with peak expression during the first postnatal week. A diffuse neuropilar staining is also prominent at P4 and P7. Immuno-electron-microscopy of layer 4 at P7 reveals restriction of FMRP to soma and dendrites, including regions near postsynaptic densities (PSDs). mGluR5 expression was restricted to dendrites and PSDs at this age. Finally, layer 4 cells from mGluR5-/- and mGluR5+/- show a decrease in spine density relative to wildtypes at P21, the opposite effect in spine density to that observed in mice lacking FMRP (Irwin et al., 2000). These findings demonstrate a role for FMRP in the differentiation of S1 and are consistent with the mGluR theory of FXS. 3.13 A molecular neuroanatomical study of the developing human neocortex from formation of the cortical plate to the arrival of thalamocortical axons in th Clowry G 1, Bayatti N 1, Moss J 1, Sun L 3, Ambrose P 1, Lindsay S 1,2 Institute of Neuroscience and the , School of Clinical Medical Sciences1, Institute of Human Genetics2, School of Biology and Psychology3, Newcastle University, Newcastle upon Tyne, By studying multiple protein expression patterns by immunohistochemistry we have correlated structure with function in different compartments of the developing human cortical wall. The marginal zone exhibited intense expression of markers that indicate a dense network of neurites and synapses at all ages studied. During an initial phase of development 8-13 postconceptional weeks (PCW) the cortical plate, which expressed MAP2 and dense Nissl staining, grew rapidly, then more slowly from 13-16 PCW, although a distinct layer V expressing Er81 immunoreactivity was observed. A distinct subplate region developed from 10.5-13 PCW, rich in synaptophysin, GAP43 and vesicular GABA transporter immunoreactivity and larger than previously described at this stage. From 13 PCW the subplate rapidly expanded, becoming the largest compartment by 16 PCW and clearly visible on MRI scans of post mortem brains. It was differentiated in structure, with neuropeptide Y positive neurones found near to the cortical plate, and KCC2 immunoreactive neurones localised near to the intermediate zone. Glutamate decarboxylase and calretinin positive inhibitory neurones migrated both tangentially and radially from 11.5 PCW, with tangential migration seen largely, but not exclusively, in the subventricular zone. From 12.5 PCW the Pax6 and MAP2 immunoreactive subventricular zone differentiated into inner and outer cell rich compartments divided by a fibrous layer. The Pax6 positive, MAP2 negative ventricular zone maintained its size throughout the period studied. A spontaneously active synaptic network may exist in the subplate that guides development of migrating neurones and the newly forming cortical plate prior to the arrival of thalamocortical afferents. 3.14 A search for genes involved in specifying the early cortical map in human development Bayatti N (1), Sarma S (2), Eyre J A (1), Lindsay S (2), Clowry G J(1) (1) Neural Development Plasticity and Repair group (2) Institute of Human Genetics (IHG), Institute of Neuroscience, School of Clinical Medical Sciences, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, NE1 4LP, United Kingdom. The homeodomain transcription factor Emx2 and the paired box-containing transcription factor Pax6 are expressed in reciprocal gradients in the proliferating zones of the developing rodent neocortex and interact in setting up the early cortical map. Using in situ hybridization and immunohistochemistry we have analysed the expression of these two genes in the developing human cortex between 8-12 gestational weeks (GW) and using Affymetrix gene chips we have looked for additional candidates during human development. At 8 GW, expression of EMX2 and PAX6 was limited to the ventricular and subventricular zones (VZ, SVZ) and EMX2 exhibited a high caudomedial to low rostrolateral gradient, with PAX6 exhibiting the opposite gradient. From 9 GW EMX2 was also strongly expressed in the developing cortical plate whilst maintaining a gradient. However, PAX6 expression remained in the proliferative zones and became uniform throughout the extent of the cortical plate. Therefore at 8 GW, around the time the CP first appears, both EMX2 and PAX6 are localised to the proliferative zones and express prominent reciprocal gradients suggesting they could interact to confer early areal identity. Thus these genes exhibit only a transient co-localisation, and additional candidates that are expressed in similar gradients throughout all stages analysed were identified by gene chip analysis. For instance, two such candidates ZIC1 and NR2F1, were found to be expressed at high levels at the rostral and caudal poles of the developing human cortex respectively and expression was confirmed by in situ hybridisation (ZIC1) and immunocytochemistry (NR2F1). Supported by the Wellcome Trust. Page 4/101 - 10/05/2013 - 11:11:03
4.01 The effect of hippocampal slice orientation, on the GluK5 receptor subunit dependency of NMDA receptor independent mossy fibre LTP. Sherwood J L, Nistico R, Lodge D, Collingridge G L, Bortolotto Z A [1,2,3,4,5] MRC Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol. BS8 1TD. UK, [2] Department of Pharmacobiology and University Centre for Adaptive Disorders and Headache (UCHAD), University of Calabria, Rende, Italy, Recently it has been agreed that pre-synaptic kainate receptors play a role in the induction of NMDA receptor independent long-term potentiation (LTP) at mossy fibre (MF) synapses.1,2 However, controversy remains over the involvement of GluK5 receptor subunits.2 Our laboratory is interested in identifying sources of disparity.3 While our lab use parasagittal slices, others use transverse.2 Here we investigate the effect of hippocampal slice orientation. Parasagittal: isolated cerebral hemispheres were fixed on the base of a vibratome, lateral surface down, and sliced parallel to the brain midline. Transverse: isolated hippocampi were mounted on an agar block and sliced perpendicular to the septo-temporal axis in a vibratome. Using standard conditions,1 CA3 field potentials were recorded in stratum lucidum and evoked by constant current stimulation of the MF pathway. Efficacy of synaptic transmission was sampled every 30 s. Following 30 min baseline period, a potent and highly selective GluK5 receptor antagonist, ACET (David Jane, personal communication), was washed on for 20 minutes and LTP induction tested by delivering 100 stimuli at 100 Hz (in the presence of D-AP5 to exclude NMDA receptor-dependent LTP). We confirm that GluK5 receptor antagonism blocks NMDA receptor-independent MF LTP in parasagittal slices,1 but also that GluK5 receptor antagonism has no effect on NMDA receptorindependent LTP in transverse slices.2 4.02 Role of PICK1 in AMPA receptor trafficking events following oxygenglucose-deprivation Dixon R, Mellor J, Hanley J Department of Anatomy, School of Medical Sciences, University of Bristol, Tyndall Avenue, Bristol, BS8 1TD Ischaemia causes a downregulation in expression of GluR2 a widely expressed α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) subunit that renders AMPARs largely impermeable to calcium. Changes in total GluR2 protein expression have been observed 24-48 hours post-ischaemia, but changes in AMPAR trafficking that occur straight after an ischaemic episode have been less widely studied. Using oxygenglucose-deprivation (OGD) to mimic ischaemia in vitro, we show a rapid shift in surface AMPAR subunit composition following OGD in hippocampal cultures. Surface protein levels of GluR2-containing-AMPARs are significantly reduced immediately after a 30 minute period of OGD, whereas total GluR2 and surface GluR1 levels remain the same as controls. In addition, using whole-cell patch-clamp recordings from CA1 pyramidal cells we show a decrease in rectification index (RI: +40 EPSC/- 70 EPSC) following a 30 minute period of OGD. This indicates that GluR2- containing-AMPARs are being replaced with GluR2-lacking AMPARs at CA3-CA1 synapses. In order to investigate the molecular mechanism for this trafficking event we postsynaptically infused peptides that interfere with GluR2 C-terminal interactions with PDZ-domain proteins. Infusion of pep2- EVKI which selectively blocks the PICK1-GluR2 interaction prevented the OGD-mediated decrease in RI, whilst a control peptide pep2-SVKE had no effect. This shows PICK1 to be a crucial mediator in initial trafficking events that occur post-ischaemia. This PICK-mediated change in subunit composition would lead to an increase in calcium influx through GluR2- lacking AMPARs resulting in activation of downstream cell death pathways. These results present the GluR2-PICK1 interaction as a potential novel therapeutic target in stroke treatment. 4.03 What is the significance for synaptic plasticity of the developmental change in N-methyl D-aspartate receptor subunit expression Bartlett T, Bannister N, Collett V, Massey P, Bashir Z, Fitzjohn S, Collingridge G, Lodge D MRC Centre For Synaptic Plasticity,, University Of Bristol,, School Of Medical Sciences,, University Walk,, Bristol,, UK Long term potentiation (LTP) and long term depression (LTD) are forms of synaptic plasticity important for learning and memory. In area CA1 of the hippocampus the NMDA receptor is crucial for the induction of LTP and LTD induced by high and low frequency stimulation respectively. The NMDA receptor comprises four subunits, two NR1 and two NR2 from four possible types (NR2A-NR2D). The expression of NR2 subunits is developmentally regulated, with NR2A appearing at P7 while NR2B is already high at birth (Sheng, Cummings et al. 1994). To detect if different subtypes of the NR2 subunit are involved in the induction of LTP and LTD at different stages in development we studied the effect of subunit selective antagonists on the induction of LTD induced by low frequency stimulation (1 Hz, 15 mins) and LTP induced by high frequency stimulation (100 Hz, 1 s) in area CA1 of hippocampal slices from P14 and P42-56 Wistar rats. The NR2B-selective antagonist Ro 25-6981 (Ro, 5μM) did not block LTD at either P14 or P42-P56, although the induction of LTD in the older slices required the glutamate uptake blocker, threo-βbenzylaspartic acid (TBOA). This suggests the induction of LTD is not exclusively dependent on NR1/NR2B NMDARs at either developmental stage under our experimental conditions. 4.04 Activation of muscarinic acetylcholine receptors induces LTD in the CA1 region of the hippocampus: GluR2 AMPA receptor internalisation Dickinson B, Jo J, Cho K Henry Wellcome Laboratories & , The MRC Centre for Synaptic Plasticity , Dorothy Hodgkin Building , Faculty of Medicine , University of Bristol , Whitson Street , BRISTOL BS1 3NY The cholinergic system is implicated in Alzheimer’s disease (Kasa et al, 1997). Muscarinic acetylcholine receptors (mAChRs), a subfamily of cholinergic receptors, have a critical role in synaptic plasticity in the perirhinal cortex (Massey et al, 2001) and the visual cortex (Kirkwood et al, 1999). However, the molecular mechanism of mAChR-dependent long-term depression (LTD) in the hippocampus is unknown. Using whole-cell patch recording we have shown that bath application of carbachol (CCh; 50ƒÝM for 10min) induces LTD in the CA1 of the hippocampus. Our study also confirmed that inclusion of the Ca2+ chelator BAPTA (10mM) in the electrode solution blocked LTD. Thus, a postsynaptic mechanism might be involved in CCh-induced LTD. It has been hypothesised that changes in AMPA receptor-mediated synaptic transmission is a molecular mechanism of LTD. Therefore, we next determined if CCh-induced LTD is due to the internalization of AMPA receptors. Postsynaptic inclusion of PEP2-SVKI (YNVYGIESVKI), a peptide analogous to the interaction site of GRIP and PICK with the GluR2 subunit of AMPA receptors (Daw et al., 2000), was shown to block LTD. However, the addition of the control peptide PEP2-SVKE (NVYGIESVKE) has no effect on CCh-induced LTD. In conclusion, the data suggest that AMPA receptor internalisation has a role in CCh-induced LTD in the CA1 of the hippocampus. 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37.01 Nitric oxide inhibition incre
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39.06 The role of glutamate recepto
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40.03 Live imaging of Per1 driven G
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43.10 Biochemical estimates of SNAR
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45.01 Mutant SOD1-PUMA knockout dou
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49.04 Regulation of synaptic functi
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51.04 The use of MRI for tracking d
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56.06 Dissecting exploratory behavi
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57.01 Opioid Receptor Agonists’-
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57.09 Cognitive rigidity and altere
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57.17 An analysis of DJ-1 (PARK7) a
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58.05 Differential effects of Inter
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59.05 Blockade of paw incision-indu
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60.07 2-Dimensional gel electrophor
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63.02 Subpyrogenic systemic inflamm
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64.08 Modulation of ketamine-induce
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65.08 The anti-inflammatory role of
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68.01 A comparison of carbachol and
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