Neurosteroid Regulation of Seizures

描述（由申请人提供）：女性占癫痫患者的大多数，其中许多人在月经周期期间经历与血清孕酮和雌激素水平的周期性变化相关的癫痫发作周期性加重。这种情况被称为月经性癫痫。目前，还没有经过科学检验的有效治疗月经恶化的方法。在一项多中心试验中，黄体酮治疗月经期癫痫未能显示疗效。我们已经开发了一种慢性颞叶癫痫的雌性大鼠模型，并将使用该模型来研究长期孕酮暴露对兴奋性和抑制性突触传递以及癫痫发作频率和强度的影响。具体来说，我们将测试我们的假设，在雌性动物孕酮的慢性升高减少了抗惊厥作用的孕酮通过增强AMPA受体介导的突触传递和抑制GABAA受体介导的突触传递。在目的1中，我们将确定孕激素治疗对幼稚和癫痫雌性大鼠海马主要神经元的突触传递的影响，使用膜片钳电生理学和分析AMPA受体亚单位的表达，通过生物化学和免疫组织化学技术相结合。在目标2中，我们将使用与目标1中类似的技术组合来确定孕酮处理对幼稚和癫痫雌性大鼠海马主要神经元上GABA能突触传递的影响。在目标3中，我们将确定孕酮受体在孕酮治疗和停药期间孕酮诱导的耐受中的作用。这些研究将为月经性癫痫的发病机制提供新的见解。这些研究可以解释孕激素治疗月经期癫痫失败的机制，并可能确定治疗月经期癫痫发作加重的新的治疗靶点。

DESCRIPTION (provided by applicant): Women constitute a majority of the patients with epilepsy, and many of them experience a cyclical exacerbation of seizures related to periodic changes in serum progesterone and estrogen levels during the menstrual cycle. This condition is called catamenial epilepsy. Currently, there are no scientifically tested effective treatments fr catamenial exacerbation. In a multi-center trial of progesterone therapy for catamenial epilepsy failed to show efficacy. We have developed a model of chronic temporal lobe epilepsy in female rats and will use this model to study the effect of prolonged progesterone exposure on excitatory and inhibitory synaptic transmission and on seizure frequency and intensity. Specifically, we will test our hypothesis that a chronic elevation of progesterone in female animals diminishes the anticonvulsant action of progesterone by enhancing AMPA receptor-mediated glutamatergic synaptic transmission and suppressing GABAA receptor mediated synaptic transmission. In Aim 1, we will determine the impact of progesterone treatment on glutamatergic synaptic transmission on hippocampal principal neurons in naive and epileptic female rats using a combination of patch clamp electrophysiology and analysis of the expression of the AMPA receptor subunits via both biochemical and immunohistochemical techniques. In Aim 2, we will determine the impact of progesterone treatment on GABAergic synaptic transmission on hippocampal principal neurons of naive and epileptic female rats with a similar combination of techniques as in aim 1. In Aim 3, we will determine the role of progesterone receptors in progesterone-induced tolerance during progesterone treatment and withdrawal. These studies will provide novel insights into the mechanisms of catamenial epilepsy. These studies could explain the mechanism of failure progesterone therapy for treatment of catamenial epilepsy and potentially identify novel therapeutic targets for the treatment of catamenial exacerbation of seizures.