This application is to continue basic research into membrane and synaptic mechanisms of mammalian brain aging, using a specific-pathogen-free aged rat model. Studies are conducted primarily In hippocampal slices (with some work In anesthetized animals), using a combination of voltage-damp procedures, conventional Intracellular recording, receptor analyses and quantative electron microscopy. Research during the preceding phase revealed that aged rat hippocampal neurons exhibit consistent Increases of voltage-sensitive calcium (Ca) currents, which apparently Is the cause of Impaired synaptic potentiation In these animals. Synaptic vesicle analyses showed that vesicle depletion is not the cause of Increased synaptic depression with aging. In addition, corticosteroids (CORT) were found to increase apparent Ca influx, and to do so more with aging. Several aging changes in CORT receptors were found, which could account for the greater Impact of CORT with aging. In the next phase, it is proposed to a) study the causes and nature of aging-related Increases in Ca Influx In much greater detail, using voltage- and patch-damping approaches In the slice; b) assess the role of phosphorylation In Ca channel modulation and in Ca current changes with aging; c) analyze mechanisms of aging changes in the corticosteroid modulation of Ca Influx; d) study possible changes in receptor-gated Ca channels (NMDA) with aging; and e) assess the role of these membrane current changes In modifying synaptic potentiation and depression, using Intracellular recording and quantitative E.M. analyses of vesicle patterns. These studies could clarify the basis of brain cell decline with aging and/or Alzheimer's disease, since both glucocorticoids and altered Ca homeostasis are suspected of roles in aging-dependent neuronal degeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG004542-08
Application #
3115192
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1991-05-01
Project End
1996-04-30
Budget Start
1992-05-10
Budget End
1993-04-30
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
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