The Role of Microglia in Epilepsy

摘要 我们最初的赠款资金集中在实验诱导癫痫发作后的最早时期。 我们记录了癫痫环境中小胶质细胞和神经元之间强大的物理相互作用 结论：小胶质细胞在急性癫痫发作中提供了有益的功能。在这次更新中，我们将 进一步研究癫痫脑内小胶质细胞的活性，将细胞和功能结合起来 实验性小鼠癫痫模型的电生理和行为学成像研究。我们 将从最初的资金周期扩展我们的发现，以进一步表征小胶质细胞在 癫痫发作后的大脑，并提供急性发作小胶质细胞神经保护的进一步证据 红藻氨酸(KA)诱导癫痫发作的时相。此外，我们还将研究小胶质细胞在 小胶质细胞消融联合化学致敏DREADD治疗癫痫慢性期的癫痫脑 接近了。我们的中心假设是小胶质细胞在急性脑出血急性期扮演相反的角色。 癫痫发作和癫痫的慢性期。这一假设将通过以下方式进行检验 具体目标： 在目标1中，我们将研究癫痫诱导的小胶质细胞突起的动力学和功能。 在目标2中，我们将确定小胶质细胞在癫痫发生中的作用。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，这笔赠款将扩大最初资助的结果，以阐明有益的作用。 对于癫痫急性期的小胶质细胞此外，这种更新将突出有害的 小胶质细胞在促进癫痫诱导的神经发生、神经元萌发、神经元分化中的作用 癫痫慢性期的兴奋性和自发性癫痫。这项研究不仅将改善 我们对小胶质细胞致痫机制的理解也证明了小胶质细胞是 治疗癫痫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.