Mechanisms of expression of NMDA receptor-dependent LTP and LTD in the hippocampus

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The purpose of this proposal is to establish the mechanisms responsible for the initial expression of long-term potentiation (LTP) and long-term depression (LTD) at CA1 synapses of the rat hippocampus. These forms of synaptic plasticity are believed to involve fundamental processes utilised by the brain to enable it to adapt its function on the basis of experience. The study of these forms of LTP and LTD is therefore central to our understanding of the synaptic basis of learning and memory and various brain disorders. The present work will build upon the principal applicant?s past research (funded continuously by the MRC since 1984), the work of the co-applicants and many other groups in the field to address several interrelated aspects of the roles of the AMPA receptor (AMPAR) subtype of L-glutamate receptor in LTP and LTD. We plan to test the general hypothesis that multiple forms of experience-dependent synaptic plasticity co-exist at these synapses but that they can be divided mechanistically to those that involve a change in the single channel conductance properties of AMPARs and those that affect the synaptic membrane insertion and removal of AMPARs. We believe that these two types of synaptic plasticity are regulated during development of the nervous system and may correspond to adult and developmental forms of synaptic plasticity, respectively. We intend to identify the molecular changes that underlie these forms of activity-dependent synaptic plasticity and to establish the signalling mechanisms involved. Experiments will all be conducted in vitro using hippocampal slices, dissociated hippocampal neurones and cell lines. The research will involve a highly multidisciplinary approach combining primarily electrophysiology, pharmacology, molecular biology and imaging. It will utilise the new facilities and recently assembled expertise of members of the MRC Centre for Synaptic Plasticity, to exploit recent exciting discoveries concerning the molecular regulation of AMPARs.