Many epileptic women experience an increase in the frequency or severity of seizures around the time of menstruation. These seizures, often referred to as catamenial seizures, are difficult to control and, thus, pose a significant clinical problem. Much experimental evidence suggests that the variations in plasma gonadal steroid levels that normally occur during the menstrual cycle may be significant in regulating seizure frequency. Presently, however, the means by which gonadal steroids modulate epileptiform activity are not well understood. The overall goal of the experiments described in this proposal is to better understand the mechanisms by which gonadal steroids influence epileptiform activity. Using the in vitro hippocampal slice from 288 male and female Sprague-Dawley rats as a model, and the techniques of extracellular and intracellular neurophysiological recording, we will investigate the direct effects of progesterone and estradiol on an epileptogenic focus. Specifically, we will: 1) determine if progesterone or one of its metabolites suppresses epileptiform activity in the hippocampal slice, 2) determine if estradiol potentiates epileptiform activity in the hippocampal slice, 3) investigate the mechanisms by which """"""""anticonvulsant"""""""" doses of progesterone or one of its metabolites influence neuronal activity, 4) investigate the mechanisms by which """"""""proconvulsant"""""""" and convulsant doses of estrogens influence neuronal activity, and 5) investigate the importance of the estradiol to progesterone ratio in modulating epileptiform activity.
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