Targeting Microglia in Febrile Status Epilepticus

项目总结 发热性癫痫是儿童癫痫最常见的形式。2%-5%的儿童会受到影响 年龄在6到60个月之间。它们是在体温升高时发生的，通常 与发烧有关，尽管其潜在的机制尚不完全清楚。在一个子集中 有发热性发作、惊厥和抽搐的儿童会延长，被称为发烧 癫痫持续状态(FSE)。一些经历过FSE的儿童在童年或 成年期使儿童期FSE成为随后发展为癫痫的危险因素。尽管 控制癫痫持续状态和癫痫的潜在机制已知源于 神经元功能障碍，近年来令人信服的研究表明炎症起到了作用， 广义的，在FSE中。FSE和FSE中炎性介质的增加证明了这一点 用广效抗炎药降低SE。然而，炎症，可以由 脑内的驻留细胞，如小胶质细胞和星形胶质细胞以及外周免疫细胞 可以在大脑外释放炎性介质来改变神经功能。目前的研究已经 到目前为止，还没有在FSE的背景下描述细胞特异性对炎症的贡献。在这 项目，我们已经开始确定主要居民小胶质细胞的不同贡献 FSE中大脑的免疫细胞。鉴于炎症在FSE中的广泛有害作用，它一直是 假设小胶质细胞作为炎症反应细胞，促进FSE。与这个假设相反， 我们在化学和高温诱导的SE中的初步实验结果表明， 在小鼠模型中，小胶质细胞实际上在减轻SE严重程度方面发挥了有益的作用。此外，我们有 确认小胶质细胞特异性的P2Y12R是小胶质细胞有益贡献的候选调节因子 在实验性SE期间。因此，使用成熟的小胶质细胞消除方法，我们将 现在：(1)测试一般小胶质细胞在高温诱导的SE中的作用，并确定 小胶质细胞调节SE的神经炎性环境(目标1)；(2)特异性小胶质细胞试验 P2Y12R在调节小胶质细胞对高温诱导SE的有益贡献中的作用 (目标2)；和(3)确定小胶质细胞P2Y12R在颞叶癫痫进展中的作用 (TLE)使用一种新的小鼠模型跟踪早期暴露于高温诱导的SE(目标3)。这 该项目是第一个充分阐明小胶质细胞在FSE小鼠模型中作为临床前研究对象的作用 模特。这项工作将提供一个靶向小胶质细胞的框架，作为一种新的改进方法 总体上是SE，特别是FSE。

PROJECT SUMMARY Febrile seizures are the most common form of childhood seizures. They affect 2-5% of children between the ages of 6 and 60 months. They occur with a rise in body temperature that is often associated with a fever, though the underlying mechanisms are not fully understood. In a subset of children with febrile seizure, seizures and convulsions are prolonged and are referred to as febrile status epilepticus (fSE). Some children that experience fSE go on to develop epilepsy in childhood or adulthood making childhood fSE a risk factor for subsequently developing epilepsy. Although the underlying mechanisms governing status epilepticus and epilepsy are known to emanate from neuronal dysfunction, compelling research in recent years suggest contributions from inflammation, broadly characterized, in fSE. This is evidenced by increased inflammatory mediators in fSE and reduced SE with broad-acting anti-inflammatory drugs. However, inflammation, can be generated by resident cells of the brain such as microglia and astrocytes as well as peripheral immune cells that can release inflammatory mediators outside the brain to alter neuronal function. Current research has thus far failed to delineate cell-specific contributions to inflammation in the context of fSE. In this project, we have begun to determine distinct contributions from microglia, the primary resident immune cell of the brain, in fSE. Given broadly detrimental roles for inflammation in fSE, it has been assumed that microglia, as inflammation-competent cells, promote fSE. Contrary to this assumption, our preliminary experimental results in both chemical- and hyperthermia- induced SE, indicate that microglia actually play beneficial roles in reducing SE severity in mouse models. Moreover, we have identified the microglial-specific P2Y12R as a candidate regulator of microglial beneficial contributions during experimental SE. Therefore, using well-established microglial elimination approaches, we will now: (1) test for general microglial roles in hyperthermia-induced SE and determine whether microglial regulate the neuroinflammatory environment in SE (Aim 1); (2) test for specific microglial P2Y12R roles in regulating microglial beneficial contributions to controlling hyperthermia-induced SE (Aim 2); and (3) determine microglial P2Y12R roles in the progression to temporal lobe epilepsy (TLE) using a novel mouse model follow early life exposure to hyperthermia-induced SE (Aim 3). This project is a first to adequately clarify microglial contributions in a mouse model of fSE as a pre-clinical model. This work will provide a framework for targeting microglia as a novel approach to ameliorate SE in general and fSE in particular.