The overall objective is to examine biochemical mechanisms of long-term depression of GAGAA receptor-mediated responses in CA1 pyramidal cells of the guinea-pig hippocampus, GABAA responses will be examined during: I.1. Internal perfusion of active phosphatase-2B (PP-2B). I.2. [Ca2plus]i - induced activation of calpain and PP-2B. Hypothesis: calpain induces active PP-2B by limited proteolisys. II.1. Internal perfusion of active calmodulin kinase II (CaMKII). II.2 [Ca2plus]i - induced activation of PP-2B and CaMKII. Hypothesis: PP-2B activation results in formation of active CaMKII. III.1 Internal perfusion of active protein kinase C (PKC). III.2 [Ca2plus]i - induced activation of calpain and PCK. Hypothesis: calpain mediates formation of active PCK (PKCM) via limited proteolysis. Whole-cell clamp recordings will be performed in isolated cells and cells in the hippocampal slice. Intracellular application active enzymes or elevation of [Ca2plus]i will be achieved by internal perfusion. To achieve the isolated activation of targeted enzymes by [Ca2plus]i (e.g. calpain and PP-2B in 1.2), specific inhibitors of other [Ca2plus]i - activated enzymes will be used (e.g., inhibitors for CaMKII or PKC in 1.2). Impairment of GABAA -mediated inhibition results in profound increases of excitability in situ. Such mechanism may be important in physiological (e.g. learning) and pathological (e.g. epilepsy) states of the cortex.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030144-07
Application #
2735617
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Baughman, Robert W
Project Start
1992-01-15
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Suny Downstate Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
068552207
City
Brooklyn
State
NY
Country
United States
Zip Code
11203