The Role of Microglia in Epilepsy

摘要 我们最初的拨款主要集中在实验诱发的癫痫发作后的最早时期。 我们记录了癫痫背景下小胶质细胞和神经元之间强大的物理相互作用 结论是小胶质细胞在急性癫痫发作中提供有益的功能。在这次更新中，我们将 进一步研究体内癫痫脑中的小胶质细胞活动，并将细胞和功能结合起来 实验性小鼠癫痫模型中的电生理学和行为研究成像。我们 将扩展我们最初资助周期的研究结果，以进一步描述小胶质细胞活动的特征 癫痫发作后的癫痫大脑，并提供小胶质细胞神经保护在急性发作中的进一步证据 红藻氨酸（KA）诱发的癫痫发作阶段。此外，我们将研究小胶质细胞在 使用小胶质细胞消融和化学遗传学 DREADD 治疗癫痫慢性期的癫痫脑 接近。我们的中心假设是小胶质细胞在急性期发挥相反的作用 癫痫发作和癫痫发生的慢性阶段。该假设将按以下顺序进行检验 具体目标： 在目标 1 中，我们将研究癫痫引起的小胶质细胞过程袋的动力学和功能。 在目标 2 中，我们将确定小胶质细胞对癫痫发生的贡献。最后，在目标 3 中，我们将 使用 DREADD 方法确定小胶质细胞在急性癫痫发作和慢性癫痫中的相反作用。 完成后，这笔赠款将扩展初始资金的研究结果，以阐明其有益作用 对于癫痫发作急性期的小胶质细胞 此外，这种更新将凸显有害的 小胶质细胞在促进癫痫诱发的神经发生、神经元萌芽、神经元 癫痫发作慢性期的兴奋性和自发性癫痫发作。这项研究不仅会改善 我们对小胶质细胞癫痫发生机制的理解，同时也证明小胶质细胞是 治疗癫痫发作和癫痫的潜在治疗靶点。

SUMMARY Our initial grant funding focused on the earliest period following experimentally-induced seizures. We documented robust physical interactions between microglia and neurons in epileptic contexts and concluded that microglia provide beneficial functions in the acute seizures. In this renewal, we will further investigate microglial activities in the epileptic brain in vivo and combine cellular and functional imaging with electrophysiological and behavioral studies in experimental mouse seizure models. We will extend our findings from the initial funding cycle to further characterize microglial activities in the epileptic brain following seizures and provide further evidence of microglial neuroprotection in the acute phase of kainic acid (KA)-induced seizures. In addition, we will investigate microglial roles in the epileptic brain in the chronic phase of epilepsy using microglial ablation and chemogenetic DREADD approaches. Our central hypothesis is that microglia play opposing roles during the acute phase of seizures and the chronic phase of epileptogenesis. This hypothesis will be tested along the following specific aims: In Aim 1, we will investigate the dynamics and function of seizure-induced microglial process pouches. In Aim 2, we will determine microglial contributions to epileptogenesis. Finally, in Aim 3, we will ascertain opposing microglial roles in acute seizures and chronic epilepsy using DREADD approaches. When completed, this grant will extend the findings of the initial funding to elucidate the beneficial roles for microglia in the acute phase of seizures Furthermore, this renewal will highlight detrimental contributions by microglia in promoting seizure-induced neurogenesis, neuronal sprouting, neuronal excitability and spontaneous seizures in the chronic phase of seizures. This study will not only improve our understanding of microglial mechanism to epileptogenesis but also demonstrate that microglia are potential therapeutic targets for the treatment seizures and epilepsy.