The goal of this research is to understand the roles in regulating synapse formation, function and plasticity of neurotrophins, their receptors trkA, B, and C and their downstream signaling molecules. To examine the role of neurotrophins in synapse formation, we will generate DNA constructs encoding fusion proteins in which constituents of different elements of the synapse (release zone, synaptic vesicle), such as VAMP, synapsin I, and the Ca channel beta subunit are fused to Green Fluorescent Protein (GFP). These will be injected into Xenopus embryo cells whose descendents include retinal ganglion cells. After grafting of """"""""tagged"""""""" retinal anlage from these to fresh embryos, retinal axon and synapse development will be studied in the optic tectum. Effects on synapse formation of neurotrophins and dominant negative constructs of the BDNF receptor trkB will be studied. Signaling pathways important in differentiation will be determined by injecting trkA constructs defective in interactions with individual downstream signaling molecules and determining effects of exogenous NGF. After insertion of the GFP chimeras into a defective Adenovirus, infections of murine retina will permit examination of synapse development in normal and neurotrophin-deficient mutant mice. The second project will seek to understand the molecular bases of neurotrophin regulation of exocytosis, observed by others at the Xenopus neuromuscular junction and Schaeffer collateral CA 1 synapses in the hippocampus. We will determine effects of NGF application on synaptic transmission at the Xenopus NMJ after injection of precursors with trkA. To dissect downstream signaling pathways, trkA receptors defective in activation of specific signalling pathways will be used in the same model. To further delineate a pathway, effects of dominant negative constructs of downstream signalling molecules, such PI-3 kinase and ras, will be examined. Efforts will be made to extend this analysis will be extended to a biochemically amenable system using PC12 cells expressing receptors with signalling pathway deficiencies where effects of neurotrophin application on phosphorylation of proteins associated with the exocytotic apparatus will be examined and functional consequences can be assessed.

Project Start
1999-09-01
Project End
2000-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
19
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
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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