A new role for estrogen in the central nervous system is indicated by studies demonstrating rapid changes in membrane excitability after steroid application. The onset of theses estrogen effects is too rapid to be due to the classically understood mechanism. Genomic actions require hormone binding to a nuclear receptor, interaction of the hormone receptor complex with the DNA, and triggering of new protein synthesis. Instead, rapid estrogen effects appear to e non-transcriptionaly mediated and neuromodulatory in nature. In isolated cells of the hippocampus, estrogen rapidly potentiates electrical activity induced by the excitatory neurotransmitter, glutamate. Given the importance of the hippocampus in learning and memory, and exciting new evidence that estrogen can improve cognitive skills in post-menopausal women and women with Alzheimer's disease, an understanding of the mechanisms of the rapid action of estrogene on individual cells in the hippocampus may contribute to strategies for the treatment of cognitive dysfunctions. The studies outlined in the prevent proposal apply whole cell patch clamp recording techniques to dissociated hippocampal neurons with the aim of determining sites and mechanisms of estrogen action in the potentiation of currents produced by the glutamate agonist, kainate. Proposed intracellular pathways of estrogen action will be manipulated genetically or by application of functionally and/or pharmacologically characterized agonists, antagonists, antiboies, and synthetic peptides. The following four hypotheses constitute the Specific Aims 1)estrogene potentiation of kainate-induced currents involves intracellular estrogen receptors or membrane receptors; 2)estrogene potentiates kainate-induced currents via activation of a stimulatory G-protein-coupled mechanism; 3)estrogen affects a cAMP-depdendent phosphorylation/disphosphorylation process to maintain kainate current; and, 4)estrogen potentiation of kainate-induced response involves phosphorylation of AMPA/kainate receptors by PKA. Completion of the proposed studies will reveal the intracellular pathways through which estrogen acts to exert rapid effects on an excitatory neurotransmitter in the hippocampus.
