This project developed out of studies showing that glucocorticoid (GC) hormones appeared to accelerate aspects of brain aging, neuron visibility and possibly Alzheimer's disease (AD). In addition, previous electrophysiological studies in this project found that GCs increase calcium-mediated potentials and currents (GCs are also known to influence long-term potentiation and synaptic potentials). In recent we have found that another steroid, calcitriol, also appears to influence electrophysiology and is neuroprotective. Estrogens are also known to be neuroprotective. Thus, this project will focus on identifying the electrophysiological and calcium-mediated mechanisms that underlie the effects of GCs, calcitriol and estrogens on brain aging, neuronal vulnerability and possibly Alzheimer's disease. This project will utilize two model systems, the rat hippocampal slice to study aging effects, and rat hippocampal cultured neurons, to study neuronal vulnerability. In three of the specific aims, the project will determine which electrophysiologically and pharmacologically defined currents and calcium sources are affected by the steroids, we will determine whether the effects of steroids change with aging, and will test the hypothesis that these steroid effects contribute importantly to hippocampal neuron vulnerability to glutamate-induced cell death. In two other aims, the project will attempt to identify the molecular and intracellular pathways, including those activated by kinases, that mediate steroid effects on electrophysiological properties and calcium regulation. Together, these studies are aimed at both identifying the underlying mechanisms and at clearly testing the functional relevance for aging and neurodegeneration, of steroid actions on the properties of brain neurons. These studies, therefore, should substantially clarify our understanding of the mechanisms through which brain aging and the endocrine environment increase the risk for Alzheimer's disease and other neurodegenerative disorders.
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