Book of abstracts - British Neuroscience Association

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7.01 Effect of NCAM-derived mimetic peptide, FGL, on aged-related inflammatory changes in the rat hippocampus Downer E J (1), Cowley T R(1), Berezin V A(2), Bock E(2), Lynch M A(1) (1) Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland., (2) Protein Laboratory, Institute of Molecular Pathology, Panum Institute, University of Copenhagen, Blegdamsvej 3C, 2200 Copenhagen N, Denmark. Evidence suggests that age-related cognitive deficits are associated with changes that are indicative of neuroinflammation, typified by an increase in proinflammatory cytokine production and microglial cell activation. Here we provide evidence that the neural cell adhesion molecule (NCAM)-derived mimetic peptide, FG loop (FGL), exerts anti-inflammatory effects in the hippocampus of aged rats. Male Wistar rats (3-4 months and 22 months) were divided into control and FGLtreated groups; FGL (8mg/kg) was administered subcutaneously on alternate days for 3 weeks. Following treatment rats were anaesthetized by intraperitoneal injection of urethane (1.5g/kg), sacrificed humanely, the brains rapidly removed and the hippocampus dissected free. Our data indicate that FGL attenuated the age-related increase in expression of the proinflammatory cytokine interleukin-1ß at protein and mRNA level. We also show that an age-related increase in the expression of several markers of microglial activation, MHCII, CD86, ICAM-1 and CD40, was reversed by FGL treatment. FGL was shown to enhance the hippocampal concentration of insulin-like growth factor-1 receptor (IGF-1R) and promote the transcription of the IGF-1R ligand, insulin-like growth factor-1 (IGF-1), an event likely to downregulate microglial activation. A modulatory role for FGL on IGF- 1R signalling is supported by evidence that FGL stimulated extracellular-signal-related kinase (ERK) signalling in the rat hippocampus. The inverse correlation between the markers of microglial activation and the regulatory effect of FGL on IGF-1 signalling events suggests that FGL acts as an anti-inflammatory agent in the rat hippocampus. 7.02 Pathological mutations of á-synuclein increase the rate at which it forms isoaspartate protein damage and aggregates during in vitro ageing. Vigneswara V, Ray D E, Carter W G MRC Applied Neuroscience Group,, School of Biomedical Sciences,, University of Nottingham,, Queens Medical Centre,, Nottingham,, NG7 2UH., United Kingdom., The enzyme, protein isoaspartyl O-methyltransferase (PIMT), methylates isoaspartate damage within proteins or peptides that accrues during protein ageing and/or from stressful conditions, thereby triggering damage repair. A proteomic strategy that involved detection of PIMT substrates which accumulated within PIMT knockout brain tissue enabled us to identify novel substrates for PIMT which included α-synuclein and β-synuclein (Vigneswara et al., 2006). Formation of isoaspartate within α-synuclein and β-synuclein could be mimicked by in vitro ageing of recombinant proteins. α–Synuclein formed isoaspartate at approximately 1 % of molecules per day, a rate approximately five times that of β–synuclein. Furthermore, after 20 days of in vitro ageing α-synuclein also formed isoaspartate-rich protein aggregates. Inheritable mutant forms of α–synuclein that have been linked to Parkinson’s disease pathology had both accelerated rates of isoaspartate formation and protein aggregation during recombinant protein in vitro ageing. Since protein aggregates of α–synuclein characterise (and are presumably pathogenic for) Lewy body diseases such as Parkinson’s disease, these results suggest that isoaspartate protein damage within α– synuclein may contribute to its potential to aggregate and thereby disease pathogenesis. Vigneswara, V., Lowenson, J.D., Powell, C.D., Thakur, M., Bailey, K., Clarke, S, Ray, D.E., and Carter, W.G. (2006) Journal of Biological Chemistry, 281, 32619-32629. Acknowledgements: Financial support from the EU-supported integrated project PROMEMORIA. 7.03 Aged animals show an increased threshold for LTP induction at the perforant path synapses in vivo. Cowley T R, Lynch M A TCIN,, Trinity College,, Dublin 2,, Ireland We investigated the effect of two high frequency stimulation (HFS) protocols which are regularly used to induce LTP, 250 Hz and 400 Hz, in young and aged rats. Rats were anaesthetised with urethane (1.5g/kg) and recordings were made from the medial perforant path of both hemispheres, applying the two HFS protocols contralaterally. Analysis of fEPSP slope showed that 250 Hz-HFS in a sub-population of aged rats failed to induce LTP, whereas these animals showed no deficit in response to 400 Hz. We assessed pop-spike amplitude (PSA) and found age related deficits even before titanic stimulation and subsequently the magnitude of LTP induction was diminished after either stimulation protocol. Furthermore, analysis of input/output curves was used to assess the excitability of the neurons in young compared to aged. fEPSP slope showed no significant difference, but PSA amplitude and excitability ratio showed significant impairments in aged compared to young rats. These results suggest that there is an increased threshold required to reach action potential and for the induction of LTP in a sub-population of aged rats. Paired pulse stimulation was performed before and after LTP induction with both protocols and a significant increase in facilitation of the PSA was evident only after 400 Hz-HFS at inter-stimulus intervals between 50-100 ms. These findings indicate that whereas all aged rats exhibit LTP in response to 400 Hz only a proportion similarly responded to 250Hz. 7.04 The effect of exercise on hippocampal function in young andaged male wistar rats O`Callaghan R M, Kelly A M Trinity College Institute of Neuroscience and Department of Physiology, Trinity College, Dublin 2, Ireland. Cognitive impairment is a natural consequence of age. The hippocampus is a highly plastic brain region that is particularly vulnerable to the aging process. Neurodegenerative diseases such as Alzheimer’s disease and other forms of dementia are accompanied by hippocampal dysfuntion and cognitive alteration. Current research has shown that exercise may improve neuronal function and possibly ameliorate the mental decline associated with aging by conferring protection against neurodegenerative decline or brain insult. Here we investigate the effect of a short period of forced exercise on long-term potentiation (LTP) and spatial learning in young and aged rats. We also explore the potential role of neurotrophin signalling in mediating exercise-induced effects on the brain. All experiments conformed with local and national guidelines. Following an acclimatisation period and familiarization to the exercising treadmill male Wistar rats (4 months and 22 months) were assigned to control and exercising groups. The exercise protocol involved running 1km/day on a motorised treadmill for seven consecutive days. Control rats were placed on a stationary treadmill for the same duration. A significant enhancement in LTP in the dentate gyrus (evoked by high-frequency stimulation of the perforant pathway in urethene-anaesthetized rats) was recorded in both young and aged animals who had completed the exercise protocol when compared with age-matched controls. In contrast, no significant effect of exercise on spatial learning in the Morris watermaze was observed in either young or aged populations. Parallel changes in neurotrophin signalling pathways were analysed in samples of dentate gyrus from all subject groups. Page 12/101 - 10/05/2013 - 11:11:03
8.01 Dietary flavonoids stimulate PI-3 kinase dependent antioxidant response element activity in astrocytes Bahia PK, Rattray M, Williams RJ King`s College London, The Wolfson Centre for Age-Related Diseases, Hodgkin Building, Guy`s Campus,, London SE1 1UL, Flavonoids are a large family of plant derived polyphenolic compounds with neuroprotective properties. Recent work suggests that in addition to acting as hydrogen-donors, they may also activate several protective signalling pathways to regulate gene expression. The antioxidant response element (ARE) promotes the expression of protective proteins including glutathione S-transferases. A luciferase reporter (ARE-luc) assay was used to examine whether the dietary flavan-3-ol (-)epicatechin activates this pathway in primary neurones and astrocytes. In primary cortical astrocytes, but not in neurones, (- )epicatechin (100 nM; 15min) and the human metabolite methylepicatechin, stimulated ARE-luc activity. This response was inhibited by wortmannin (150 nM) suggesting the involvement of a PI3-kinasedependent pathway. Nrf2 is a transcription factor that binds to the ARE to upregulate gene expression. The distribution of Nrf2 was examined in neurones and astrocytes by immunocytochemistry. There was clear Nrf2 immunoreactivity in cortical astrocytes but not in neurones. Nrf2 accumulated in the nucleus of astrocytes following exposure to the positive ARE modulator tBHQ (100 ЧM) and, to a lesser degree, (- )epicatechin (100 nM). Finally (-)epicatechin increased glutathione levels in astrocytes consistent with an upregulation of ARE-mediated gene expression. Together, this suggests that flavonoids may be cytoprotective by increasing the levels of antioxidant genes in addition to acting as classic free radical scavengers. Supported by the BBSRC (D20463) 8.02 Does TNF alpha promote excitotoxic neuronal death through alteration of AMPA receptor subunit composition Rainey-Smith S R, Williams R J, Rattray M A N King`s College London, Wolfson Centre for Age-Related Diseases, Guy`s Campus, London,, SE1 1UL. Amyotrophic Lateral Sclerosis (ALS), the most common motor neurone disease in human adults, is characterised by progressive paralysis with muscle wasting due to a selective degeneration of upper and lower motor neurones. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor-mediated excitotoxicity has been strongly implicated as a contributor to this selective motor neurone vulnerability. This study aims to test whether the astrocyte-derived inflammatory cytokine TNFα, produced normally in the spinal cord but upregulated in motor neurone disease, sensitises cultured mouse motor and cortical neurones to excitotoxic cell death by altering cell surface expression, subunit composition, and hence, calcium permeability of AMPA glutamate receptors. Western blotting, immunocytochemistry and RT-PCR determined AMPA receptor subunit GluR1-4 expression in 7 and 14 day old primary mouse cortical neurones. In these neurones GluR1 and 2 were abundant, while GluR3 and 4 were present at considerably lower levels. Exposure of 7 or 14 day old primary mouse cortical neurones to recombinant mouse TNFα (10 ng/ml; 15 min) increased GluR1, GluR2, and GluR4 levels in the membrane fraction with an accompanying loss in cytosolic levels, determined by immunoblotting. Cell-surface biotinylation experiments confirmed these increases. Immunocytochemistry confirmed SMI-32 positive motor neurones prepared from embryonic mouse spinal cord express the GluR1, GluR2, GluR3, and GluR4 subunits. Interestingly, exposure of these cultures to TNFα (10 ng/ml; 15 min) unmasked kainate-induced cell death. Taken together, these findings, suggest that TNFα might confer vulnerability of motor neurones to excitotoxicity by altering AMPA receptor subunit composition. 8.03 Development of biomimetic substrates to control the attachment and differentiation of neural cells Cooke M J 1, Philips S 2, Shah D S 2, Athey D 2, Lakey J H 2, Przyborski S A 1 1 School of Biological and Biomedical Sciences, University of Durham, South Road, Durham, DH1 3LE, UK, , 2 Nanotechnology Centre, Herschel Building, Newcastle Upon Tyne, NE1 7RU, UK. In situ cells are subject to many different signaling mechanisms, including; cell-cell interactions, soluble molecules and their local environmental geometry. In vitro model systems have been developed to recreate the in vivo environment and control and regulate cellular behavior using known signaling molecules. The extracellular matrix (ECM) is composed of many such signaling molecules. Cell culture substrates are often coated with ECM components such as laminin, collagen and fibronectin to enhance cell adhesion and differentiation. For example, these molecules have been shown to enhance neural cell adhesion and increase process outgrowth. However the process of coating substrates in this manner can be time consuming and has limited control and reproducibility. In this study, we in collaboration with Orla Protein Technologies, are developing novel biomimetic substrates to control cell behavior in vitro. The effects elicited by ECM molecules laminin, collagen and fibronectin can be attributed to motifs within the molecules which can be presented to cells using a biomimetic substrate. In this way we mimic the interaction between cells and their local environment experienced in tissues. We have evaluated the application of this technology on cell adhesion and differentiation using the well established rat pheocytochroma (PC12) cell line. Our data indicate that this technology can be used to control cell attachment to glass substrates and demonstrate that this approach can be used to control process outgrowth by PC12 cells following nerve growth factor induced differentiation. We propose this system as an alternative method for consistent and robust differentiation of PC12 cells. 8.04 Physiological electric fields direct hippocampal neuron migration cathodally Yao L 1,2, McCaig C 1, Zhao M 1 1School of Medical Sciences, University of Aberdeen, Aberdeen, UK; 2 National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland Introduction Initiation and effectiveness of neuron migration to the right places are critical for the development and repair of central nervous system. Endogenous electric fields (EFs) are widespread in developing and regenerating tissues. Application of EFs directs cell migration of many types of cells. However, whether applied EFs can direct neuron migration has not been demonstrated. Materials and methods Dissociated rat hippocampal neurons and microexplants were cultured on poly-L-lysine and laminin coated dishes and were identified with MAP-2 staining. The neurons were exposed to small applied electric fields and the migration was recorded with an imaging system. Results 1. In a DC EF, dissociated rat hippocampal neurons migrate to the cathode. The migration direction was reversed when the EF polarity was reversed. 2. The cathodal migration of hippocampal neurons is voltage and time dependent. A DC EF does not have significant influence on neuronal migration speed. 3. The guidance effect of EFs is also seen in neuronal migration from hippocampal micro-explants. Neurons from micro-explants migrated to the cathode. 4. EFs direct growth cone path finding and neurite orientation. Leading process branching, turning and swapping over of leading and trailing processes are the main types of neurite re-orientation. Conclusion This study demonstrates that EFs can direct rat hippocampal neuron migration cathodally. This raises the possibilities that EFs may be used as a potential cue to direct neuronal migration in repair of central nervous system. Page 13/101 - 10/05/2013 - 11:11:03
Page 1 and 2: 1.0 Paths to recovery: Modulating P
Page 3 and 4: 3.07 Congenital hypothyroidism alte
Page 5 and 6: 4.01 The effect of hippocampal slic
Page 7 and 8: 4.09 ß-adrenergic modulation of in
Page 9 and 10: 5.03 Constitutively active Ras and
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Page 15 and 16: 9.04 Inducing neural differentiatio
Page 17 and 18: 10.02 The effect of PAT (thymulin r
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Page 25 and 26: 13.06 Contribution of synaptic cond
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Page 29 and 30: 16.03 Quantitative analysis of memb
Page 31 and 32: 18.03 Finding cells for replacement
Page 33 and 34: 20.01 Cannabinoid neuropharmacology
Page 35 and 36: 21.05 Spatial arrangement of cortic
Page 37 and 38: 23.04 Adenosine, astrogliosis and e
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41.01 A polymorphism at the 3’ un
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43.02 Neuroleptic treatment worsens
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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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47.03 VAP proteins Skehel P Center
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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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53.04 The role of the pedunculopont
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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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69.06 Comparison of data analysis t
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