The primary focus of this proposal will be on the role of protein phosphorylation in long-term potential (LTP) in the rat hippocampus. Protein phosphorylation is widely recognized as the primary mechanism for post-translational control of protein activity in eukaryotes. In addition a substantial body of correlative evidence indicates that protein phosphorylation plays an important role in neuronal function. LTP is generally considered to be a form of plasticity ideally suited to serve as a substrate for more complex cognitive functions. The current proposal is designed to provide direct evidence concerning the physiological role(s), if any, played by specific phosphoproteins in long-term potentiation. The first stage of this proposal will consist of attempts to identify, with direct analytical techniques, proteins which exhibit changes in phosphorylation state that are correlated with induction of LTP. This stage is required because all previous studies of the relationship between LTP and protein phosphorylation have used indirect assays which provided particularly equivocal data. The phosphoproteins identified in the first stage. This will include purification of the proteins, preparation of antibodies specific for the proteins, and identification and purification of the kinases and phosphatases that influence the phosphorylation state of the proteins. The final stage will be devoted to studies designed to directly test the hypothesis that the proteins studied in the first two stages play a role in triggering some the plastic changes that are characteristic of LTP. The studies in this section will utilize axonal transport in crushed axons to introduce agents (e.g. antibodies and protein kinases) which influence the phosphorylatability of specific proteins into the presynaptic terminals of Schaffer collateral/commissural synapses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026377-02
Application #
3412185
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1988-07-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Bergman, H; Browning, M; Granholm, A C (1992) Development of synapsin I and synapsin II in intraocular hippocampal transplants. Hippocampus 2:339-47
Leidenheimer, N J; Browning, M D; Harris, R A (1991) GABAA receptor phosphorylation: multiple sites, actions and artifacts. Trends Pharmacol Sci 12:84-7
Parfitt, K D; Hoffer, B J; Browning, M D (1991) Norepinephrine and isoproterenol increase the phosphorylation of synapsin I and synapsin II in dentate slices of young but not aged Fisher 344 rats. Proc Natl Acad Sci U S A 88:2361-5
Browning, M D; Bureau, M; Dudek, E M et al. (1990) Protein kinase C and cAMP-dependent protein kinase phosphorylate the beta subunit of the purified gamma-aminobutyric acid A receptor. Proc Natl Acad Sci U S A 87:1315-8