Although it has become increasingly evident in the last decade that steroid hormones can modulate neuronal activity via non-genomic, short-latency effects, little is known about the mechanisms underlying these effects. The goal of this project is to investigate the cellular mechanisms by which gonadal steroids produce direct, short-latency changes in neuronal activity. We will study these mechanisms in the hippocampus and the cerebellum, two regions of the brain in which steroid hormones have been demonstrated to produce rapid alterations (within minutes) in neuronal activity. Our major objectives will be to investigate the mechanisms by which: a) estrone-3-sulfate, an estradiol metabolite, produces epileptiform activity in the hippocampal slice and b) estradiol-17-beta and estrone modulate glutamate-mediated neurotransmission in the cerebellar slice. The first objective expands our current studies of the mechanism of action of estrone-3-sulfate, and the second objective extends our investigations into other regions of the brain which have been shown to be directly influenced by estrogens. We will use intracellular and whole-cell patch clamp techniques and the in vitro brain slice to: 1) determine if physiological or pharmacological doses of estrone-3-sulfate suppress gamma-aminobutyric acid-mediated inhibition of CA1 pyramidal neurons in the hippocampal slice, 2) determine if physiological and pharmacological doses of estrone-3-sulfate suppress glutamate-mediated excitation of CA1 pyramidal cells in the hippocampal slice, 3) investigate the mechanisms by which estrone-3-sulfate alters the resting membrane potential of CA1 pyramidal cells, and 4) investigate the mechanisms by which estradiol-17-beta and estrone potentiate glutamate- mediated excitation of cerebellar Purkinje cells in the cerebellar slice. The results of these studies should provide us with further insight into the means by which gondal steroids modulate both normal and pathological processes in the central nervous system.
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