Differential roles of neuronal and astrocytic aromatase in status epilepticus and chronic epilepsy

项目总结 雌激素和癫痫之间的关系早已被认为是雌激素，如雌二醇， 主要与惊厥前效应有关。传统上，卵巢是最受关注的来源 雌二醇，特别是在月经发作加重与某些雌二醇相关的情况下- 女性月经周期的主要阶段。然而，大脑本身就是这两种物质中雌激素的来源 性别。雌二醇是由睾酮在芳香酶的作用下合成的，这种酶在 大脑，特别是在与癫痫有强烈关联的区域。在海马体中，芳香化酶几乎是唯一的 在基础状态下，星形胶质细胞在神经元中表达，但在损伤或中风等创伤后，星形胶质细胞也可以显示 高水平的芳香酶表达。脑源性雌二醇在癫痫中的作用，以及脑源性雌二醇在癫痫中的具体作用 在这种关系中，神经元和星形胶质细胞作为雌二醇的来源仍然不清楚。拟议的研究将 解决关于芳香酶和雌激素合成的相对贡献方面的主要知识空白 神经元与星形胶质细胞与癫痫持续状态(SE)和慢性癫痫发作活动的关系 癫痫，自发性反复发作的状态。我们的理论基础是，理解 神经元和星形胶质细胞作为雌激素的来源在SE和癫痫的不同阶段将使发育成为可能 新的治疗策略，选择性地针对脑源性雌激素的产生，并最大限度地增加癫痫发作- 抑制效应，同时将对突触功能和记忆的有害影响降至最低。我们将用一本小说 转基因小鼠与受控细胞特异性芳香化酶还原相结合，结合24小时 癫痫的视频脑电监测、多标记免疫荧光显微镜和生化测量 以检验我们的总体假设，即神经元和星形胶质细胞具有不同的作用， 癫痫和慢性癫痫患者海马区雌二醇的来源。在目标1中，我们将定义 海马神经元和星形胶质细胞芳香化酶表达与SE、癫痫发生和慢性癫痫的关系 癫痫。在目标2和目标3中，我们将确定海马神经元和星形胶质细胞芳香化酶在SE中的作用 易感性和慢性癫痫分别为。这些研究将使用癫痫的小鼠模型 概述了人类颞叶癫痫的几个关键的脑电和组织病理学特征。这些研究 通过提供对芳香酶表达动态的新见解，将对翻译产生积极的影响 SE和慢性癫痫中的神经元和星形胶质细胞，从而解决2020年NINDS的多个目标 癫痫研究基准，以了解癫痫的原因和相关的神经疾病，以防止 控制癫痫的进展，改善治疗方案，同时将副作用降至最低。

PROJECT SUMMARY A relationship between estrogens and epilepsy has long been acknowledged with estrogens, such as estradiol, primarily linked to proconvulsant effects. The ovaries traditionally receive the most attention as sources of estradiol, particularly in the context of catamenial seizure exacerbations in association with certain estradiol- dominant phases of the menstrual cycle in women. However, the brain itself is a source of estradiol in both sexes. Estradiol is synthesized from testosterone by the aromatase enzyme, which is highly expressed in the brain, particularly in areas strongly implicated in epilepsy. In the hippocampus, aromatase is almost exclusively expressed in neurons in basal conditions, but after trauma such as injury or stroke, astrocytes can also show high levels of aromatase expression. Roles for brain-derived estradiol in epilepsy, and the specific roles of neurons and astrocytes as sources of estradiol in this relationship, remain unclear. The proposed research will address major gaps in knowledge regarding the relative contributions of aromatase and estrogen synthesis in neurons vs. astrocytes in relation to two distinct states of seizure activity: status epilepticus (SE) and chronic epilepsy, the state of spontaneous recurrent seizures. Our rationale is that understanding distinct roles of neurons and astrocytes as sources of estrogens at different phases of SE and epilepsy will enable development of new therapeutic strategies to selectively target production of brain-derived estrogens and maximize seizure- suppressive effects, while minimizing deleterious effects on synaptic function and memory. We will use a novel combination of transgenic mice and controlled cell-specific reduction of aromatase, in combination with 24-hour video-EEG monitoring of seizures, multilabel immunofluorescence microscopy, and biochemical measurement of hippocampal estradiol to test our overall hypothesis that neurons and astrocytes have differential roles as sources of hippocampal estradiol in SE and chronic epilepsy. In Aim 1, we will define the temporal dynamics of hippocampal neuronal and astrocytic aromatase expression in association with SE, epileptogenesis, and chronic epilepsy. In Aims 2 and 3, we will determine the roles of hippocampal neuronal vs. astrocytic aromatase in SE susceptibility and chronic epilepsy, respectively. These studies will use a mouse model of epilepsy that recapitulates several critical EEG and histopathological features of human temporal lobe epilepsy. These studies will have positive translational impact by providing new insights into the dynamics of aromatase expression in neurons and astrocytes in SE and chronic epilepsy, and thereby address multiple goals of the 2020 NINDS Epilepsy Research Benchmarks to understand causes of epilepsy and related neurologic conditions, to prevent the progression of epilepsy, and improve treatment options while minimizing side effects.