Molecular mechanisms of long-term Depression in the hippocampus

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Synaptic plasticity is the process by which synapses can alter their efficiency of transmission; the two main forms are long-term potentiation (LTP) and long-term depression (LTD). The principal excitatory neurotransmitter in the brain, L-glutamate, exerts its physiological actions via three types of ionotropic receptors, named after the agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate, as well as a family of G-protein coupled, metabotropic glutamate receptors (mGluRs). Since the discovery that NMDA receptors (NMDARs) are the trigger for LTP at CA1 synapses in the hippocampus, and that they are involved in hippocampus-dependent learning and memory, it has become very evident that NMDAR-dependent LTP (NMDAR-LTP) is critical for a variety of cognitive processes. More recently, evidence has been accumulating for the importance of LTD, triggered by the activation of NMDARs or mGluRs, in various forms of learning and memory. These plastic processes are critical throughout life, from the connections made during development through to explicit forms of learning and memory into adulthood. Increasingly it is being realised that alterations in LTP and LTD contribute in various ways to a variety of neurological and psychiatric disorders, such as dementia, epilepsy, depression and schizophrenia. We and others have recently made molecular links between plasticity and disease, which suggests that dysregulation in synaptic plasticity may directly contribute to the aetiology of a number of neurological pathologies. For example, in the process of studying mechanisms of LTD in the hippocampus, we have recently identified key roles for a number of proteins that are linked to neuropathogies, including glycogen synthase kinase-3beta (GSK-3beta). We now plan to address several key unanswered questions concerning molecular mechanisms of NMDAR-LTD and mGluR-LTD in the hippocampus, with a focus on phosphorylation cascades, Ca2+ signalling and glutamate receptor trafficking. Based on extensive pilot data we plan to establish new components of molecular pathways underlying different forms of LTD, and to deduce precisely how induction of LTD, and the accompanying transient increase in cytosolic Ca2+, results in alterations in the synaptic expression of glutamate receptors. A key new development for our work will be the study of LTD in adult mice in vivo. We plan to establish how the signalling cascades that have been identified in simplified preparations operate in the intact animal. These findings will contribute to a fuller understanding of the molecular basis of major forms of synaptic plasticity in the brain, work that is directly relevant to a substantial number of major brain disorders