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4.13 Regulation of Egr1 and Egr3 following the induction of LTP in CA1 of the hippocampus. Cheval H, Laroche S, Davis S NAMC, UMR 8620, CNRS, Univ Paris-Sud, 91405 Orsay, France The gene encoding Egr1 (zif268) is regulated and necessary for late phases of LTP in dentate gyrus and the consolidation of a number of different forms of memory. Very little data exists about the potential role of Egr1 and other members of this family of transcription factors in plasticity in CA1. We have examined regulation of both Egr1 and Egr3 following the induction of LTP in CA1 in both rats and Egr1-/- and +/+ mice. Preliminary evidence shows LTP induced in +/+ mice is associated with an increase in Egr1 protein levels. However, regulation of the protein is not specific to LTP as pseudotetanus also induces an increase in Egr1 protein level. In mutant mice, LTP is attenuated and western blotting confirms the lack of protein, suggesting that Egr1 is neither necessary nor specific to LTP in CA1. Induction of LTP also induced a similar pattern of overexpression of Egr3 in both wildtype and mutant mice with regulation of the protein restricted to the ƒÑ isoform, suggesting that Egr3 regulation may be linked with regulation of Egr1. As a transcription factor, Egr1/Egr3 presumably bind to downstream gene targets with a consensus ERE sequence on their promoter. We are conducting EMSA and supershift assays in rat to determine whether Egr1 and Egr3 functional binding to promoter regions sequences is increased following induction of LTP. Preliminary evidence suggests this to be the case and supershift experiments will be conduced to examine the specificity of Egr1 and Egr3 binding to the ERE sequence. 4.14 Multielectrode array-based platform for analysis of the synaptic transmission and plasticity phenotypes in mutant mice Kopanitsa MV, Afinowi NO, Grant SGN Genes to Cognition Programme, The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA The Genes to Cognition Programme (G2C, www.genes2cognition.org) is a multidisciplinary initiative to study genes involved in brain functions and behaviour. An important part of G2C is production and characterisation of transgenic mice. We sought to employ multielectrode array (MEA) technology for the high-throughput electrophysiological assessment of mutant animals. We have shown previously (Kopanitsa et al., BMC Neuroscience 7: 61) that MEAs allow for efficient recording of synaptic potentials and facilitate LTP studies in hippocampal slices. To further validate MEA-based approaches, we studied several mutants where deficiencies in LTP had been documented. Synaptic responses were recorded in the CA1 area of hippocampal slices upon stimulation of Schäffer collaterals. LTP was induced in one of the two stimulated pathways by high frequency tetani and/or by theta-burst stimulation. We have observed deficient LTP phenotypes in GluR-A -/-; SynGAP +/- and NR2A ΔC/ΔC mice, which was consistent with published reports. Also, we found a decrease of LTP in the NR2B/ΔC mice, which suggested that integrity of cytoplasmic tails of both NR2A and NR2B subunits is important for plasticity. The MEA-based platform was also used to investigate synaptic transmission and LTP in a number of novel strains created in our lab. We conclude that MEA technology is a rapid and efficient platform for analysis of synaptic transmission and plasticity in mutant mice. In addition to the throughput, an advantage of MEAs is that they allow standardising recording conditions during LTP experiment, which is extremely important for comparing the severity of different mutant phenotypes. 5.01 Human bone marrow stromal cells promote nerve growth over the major nerve-inhibitory molecules found in the injured spinal cord. Wright K T, El Masri W, Osman A, Roberts S, Chamberlain G, Ashton BA, Johnson WE Centre for Spinal Studies, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, Shropshire SY10 7AG, UK; Institute for Science and Technology in Medicine, Keele University, Keele, Staffordshire ST5 5BG, UK. Chondroitin sulphated proteoglycans (CSPG), myelin associated glycoprotein (MAG) and Nogo inhibit nerve growth in vivo. Their inhibitory influence in spinal cord injury (SCI) has been shown in animal models wherein treatments that reduced their presence, integrity or blocked their activity promoted axonal regeneration and functional recovery. Transplantation of bone marrow stromal cells (MSC) into the injured spinal cord induced similar results, but it is still unclear how the improvements noted in these animals were achieved. We have examined the potential for human MSC isolated from SCI patients to promote nerve growth across inhibitory molecules using an established in vitro model of nerve growth. As previously described CSPG, MAG and Nogo were each found to inhibit neurite outgrowth in a concentration dependant manner, this effect was diminished in the presence of MSC. Time-lapse video microscopy demonstrated that MSC acted as “cellular bridges” and also “towed” neurites over inhibitory substrates. Whereas conditioned medium from MSC cultures stimulated neurite outgrowth over type I collagen, it did not promote outgrowth over CSPG, MAG or Nogo. 5.02 Mesenchymal stem cell- derived soluble factors and their instructive effects on neural stem and progenitor cells Hardy S A, Croft A P, Przyborski S A 1School of Biological and Biomedical Sciences, University of Durham, South Road, Durham, DH1 3LE; 2ReInnervate Ltd, Durham, DH1 3HP Mesenchymal stem cell (MSC) transplantation in animal models of neurological disease has resulted in neurological improvement, however, the mechanism by which this occurs is under debate. Evidence suggests that MSCs have neurogenic potential and undergo differentiation into neural tissue to replace cells damaged in disease (trans-differentiation). These data are conflicting as others argue that MSCs do not transdifferentate but instead fuse with host cells adopting their phenotype. However, both mechanisms are unlikely to fully account for the improvements seen. We are currently investigating a third mechanism whereby transplanted MSCs promote endogenous repair of neurologically damaged areas by the release of trophic factors and cytokines e.g. NGF and BDNF. We have shown that MSCs produce factors that instruct neural stem cells (NSCs) to adopt neuronal and glial lineages, and this is dependent on the developmental status of the MSC. Under standard culture conditions MSCs are negative for neural antigens, and produce factors which instruct NSCs to adopt a predominantly astrocytic fate. Conversely, we have shown that MSCs induced to form neurosphere-like structures, which are positive for neural antigens such as nestin and GFAP, instruct NSCs to adopt a predominantly neuronal fate. Such events are likely to contribute to the functional improvements observed in disease models following MSC transplantation. We are currently in the preliminary stages of identifying these unknown factors. These findings suggest that MSC transplantation may promote axonal regeneration by stimulating nerve growth via secreted factors and also by reducing the nerve-inhibitory effects of extracellular molecules. Further experimentation using this model will help identify how MSC are able to migrate over nerve-inhibitory molecules and how they stimulate co-localised nerve growth. This thereby may permit appropriate molecular targeting to further enhance nerve growth in vivo. Page 8/101 - 10/05/2013 - 11:11:03
5.03 Constitutively active Ras and dominant negative MEK1 improve functional recovery following C4 dorsal hemisection in mice Makwana M (1), Anderson P N (2), Hristova M(1), Zbarsky V (1), Miller F D (3), Kaplan D (3), Heumann R (4), Raivich G (1,2) 1. Centre for Perinatal Brain Protection and Repair, Dept of Obstetrics & Gynaecology, University College London, UK, 2. Dept of Anatomy, University College London,UK, 3. Univ of Toronto, Sick Children Hospital, Toronto, Canada, 4. Dept of Neurobiochemistry, Ruhr- University Bochum, Germany, The extracellular-signal-regulated-kinase cascade is important in neuronal survival and plasticity. To determine the function of neuronal Ras and MEK in axonal regeneration, we generated constitutively active Ras (Ras+), dominant-negative MEK1 (MEK1dn) and Ras+xMEK1dn double mutant (DM) transgenic mice. Studies in these mutants have shown extensive collateral sprouting of corticospinal tract (CST) axons, rostral to the lesion in the grey and white matter on the ipsilateral side in Ras+, MEK1dn and DM animals compared with wild-type (WT) controls. Rearing and grid-walk tests were used to test functional recovery over a period of 28 days following a unilateral left dorsal hemisection (DH) at C4, followed by labelling of the CST with biotinylated dextran amine to assess the sprouting response. Ras+ and MEK1dn groups performed significantly better in left forepaw use than WT in the rearing test at day 14 (35.0%±9.0%; 45.0%±7.0% versus 9.0%±5.0%; mean±SEM respectively; **p
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Page 3 and 4: 3.07 Congenital hypothyroidism alte
Page 5 and 6: 4.01 The effect of hippocampal slic
Page 7: 4.09 ß-adrenergic modulation of in
Page 11 and 12: 6.07 Proteomic identification of bi
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Page 15 and 16: 9.04 Inducing neural differentiatio
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Page 31 and 32: 18.03 Finding cells for replacement
Page 33 and 34: 20.01 Cannabinoid neuropharmacology
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Page 37 and 38: 23.04 Adenosine, astrogliosis and e
Page 39 and 40: 25.04 The L1 cell adhesion family a
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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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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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