Targeting Microglia in Febrile Status Epilepticus

项目摘要 热性惊厥是儿童惊厥最常见的形式。影响2-5%的儿童 在6到60个月之间。它们发生时体温升高， 与发烧有关，尽管其潜在机制尚未完全了解。的子集中 儿童热性惊厥，惊厥和抽搐是长期的，并被称为发热 癫痫持续状态（fSE）。一些经历fSE的儿童在童年时期继续发展癫痫， 成年期使儿童fSE成为随后发生癫痫的危险因素。虽然 已知控制癫痫持续状态和癫痫的潜在机制源自 神经元功能障碍，近年来令人信服的研究表明炎症的贡献， 广泛的特点，在fSE。这通过fSE中增加的炎症介质和 广泛作用的抗炎药可降低SE。然而，炎症，可以产生的 脑的常驻细胞如小胶质细胞和星形胶质细胞以及 可以在脑外释放炎性介质以改变神经元功能。目前的研究 迄今为止，未能描述在fSE的情况下细胞特异性对炎症的贡献。在这 项目，我们已经开始确定不同的贡献，从小胶质细胞，主要居民 大脑的免疫细胞，以fSE表示。鉴于炎症在fSE中的广泛有害作用， 假设小胶质细胞作为炎症感受态细胞促进fSE。与这一假设相反， 我们对化学和高温诱导的SE的初步实验结果表明， 小胶质细胞实际上在降低小鼠模型中SE严重程度方面发挥有益作用。而且我们 确定了小胶质细胞特异性P2 Y12 R作为小胶质细胞有益贡献的候选调节因子 在实验性SE中。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血压诱导的SE中的作用，并确定是否 小胶质细胞调节SE的神经炎症环境（目的1）;（2）检测特异性小胶质细胞 P2 Y12 R在调节小胶质细胞对控制高血压诱导的SE的有益贡献中的作用 (Aim 2）;（3）确定小胶质细胞P2 Y12 R在颞叶癫痫进展中的作用 (TLE)使用一种新的小鼠模型，跟踪早期暴露于高血压诱导的SE（目的3）。这 该项目是第一个充分阐明小胶质细胞在临床前fSE小鼠模型中的作用的项目 模型这项工作将为靶向小胶质细胞提供一个框架，作为改善 一般来说是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.