We will investigate development, function and plasticity of the synapse in projects that depend on sharing expertise between the principal investigators and upon a shared mouse transgenic core. Edwards and Copenhagen will characterize the molecular pathways controlling the cycling of glutamate, the major excitatory transmitter in the CNS. They will identify the transporters involved in glutamate uptake into glia in the brain and retina, test genetically the role of glutamine synthetase in converting glutamate to glutamine, and examine the roles of glutamine transporters in controlling release from astroglia and reuptake by neurons of glutamine. Edwards will extend his studies to identification of substrates for two additional putative transport proteins that have been shown genetically to be important regulators of synaptic function--the synaptic vesicle constituent SV2 and a mammalian homologue of Drosophila diphthong first identified genetically in the laboratory of Graeme Davis. Identification of their substrates should help characterize the biochemical pathways that are disrupted by their absence. Nicoll will characterize the molecular mechanisms that underlie establishment of long-term potentiation at mossy fiber-pyramidal cell synapses in the hippocampus. He will examine the roles of presynaptic kainate acid receptors, A1 adenosine receptors, and the hyperpolarization-activated nonselective cation channel Ih in expression of LTP at this synapse. Copenhagen, Reichardt and Stryker will characterize essential roles for neurotrophin signaling in synapse establishment, function and plasticity in the retina, cerebellum, and visual cortex. They will identify the cells that require TrkB signaling for synapse development and/or function and will characterize the effects of this signaling pathway on structures of axons and dendrites in addition to those of synapses. Stryker will also characterize the roles of tyrosine kinases and proteins involved in Ca2+-mediated and cAMP-mediated signaling by examining the development of cortical topography by imaging receptive field properties in mutant mice. Dr. Davis will characterize pathways that regulate glutamate receptor clustering and postsynaptic differentiation in Drosophila, focusing on the roles of the protein kinase PAK, the adapter molecule DOCK/NCK and proteins involved in their signaling pathways.
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