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中与血清黄体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。这种情况被称为枕骨癫痫。目前，还没有经过科学检验的治疗羊膜恶化的有效方法。在一项多中心试验中，黄体酮治疗晚眠性癫痫未能显示出疗效。我们建立了雌性大鼠慢性颞叶癫痫模型，并将利用该模型研究长时间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，我们将验证我们的假设，即雌性动物体内黄体酮的长期升高会通过增强AMPA受体介导的谷氨酸能突触传递和抑制GABAA受体介导的突触传递来减弱黄体酮的抗惊厥作用。在Aim 1中，我们将结合膜片钳电生理学和生化和免疫组织化学技术分析AMPA受体亚基的表达，确定黄体酮治疗对幼年和癫痫雌性大鼠海马主要神经元谷氨酸能突触传递的影响。在目的2中，我们将采用与目的1中类似的技术组合，确定黄体酮治疗对幼稚和癫痫雌性大鼠海马主神经元gaba能突触传递的影响。在Aim 3中，我们将确定在孕激素治疗和停药期间孕激素受体在孕激素诱导耐受中的作用。这些研究将为夜床性癫痫的机制提供新的见解。这些研究可以解释黄体酮治疗双眠性癫痫失败的机制，并有可能为治疗双眠性癫痫发作加重找到新的治疗靶点。

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.