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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS016033-23
Application #
6765774
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Talley, Edmund M
Project Start
1980-04-01
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
23
Fiscal Year
2004
Total Cost
$1,102,678
Indirect Cost
Name
University of California San Francisco
Department
Physiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Chen, Albert I; Zang, Keling; Masliah, Eliezer et al. (2016) Glutamatergic axon-derived BDNF controls GABAergic synaptic differentiation in the cerebellum. Sci Rep 6:20201
Nicoll, Roger A; Roche, Katherine W (2013) Long-term potentiation: peeling the onion. Neuropharmacology 74:18-22
Herring, Bruce E; Shi, Yun; Suh, Young Ho et al. (2013) Cornichon proteins determine the subunit composition of synaptic AMPA receptors. Neuron 77:1083-96
Vigers, A J; Amin, D S; Talley-Farnham, T et al. (2012) Sustained expression of brain-derived neurotrophic factor is required for maintenance of dendritic spines and normal behavior. Neuroscience 212:1-18
Sanchez-Ortiz, Efrain; Yui, Daishi; Song, Dongli et al. (2012) TrkA gene ablation in basal forebrain results in dysfunction of the cholinergic circuitry. J Neurosci 32:4065-79
Baydyuk, Maryna; Russell, Theron; Liao, Guey-Ying et al. (2011) TrkB receptor controls striatal formation by regulating the number of newborn striatal neurons. Proc Natl Acad Sci U S A 108:1669-74
Chen, Albert I; Nguyen, Cindy N; Copenhagen, David R et al. (2011) TrkB (tropomyosin-related kinase B) controls the assembly and maintenance of GABAergic synapses in the cerebellar cortex. J Neurosci 31:2769-80
Blankenship, Aaron G; Ford, Kevin J; Johnson, Juliette et al. (2009) Synaptic and extrasynaptic factors governing glutamatergic retinal waves. Neuron 62:230-41
Arikkath, Jyothi; Peng, I-Feng; Ng, Yu Gie et al. (2009) Delta-catenin regulates spine and synapse morphogenesis and function in hippocampal neurons during development. J Neurosci 29:5435-42
Grishanin, Ruslan N; Yang, Haidong; Liu, Xiaorong et al. (2008) Retinal TrkB receptors regulate neural development in the inner, but not outer, retina. Mol Cell Neurosci 38:431-43

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