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The Role of Microglia in Epilepsy

小胶质细胞在癫痫中的作用

基本信息

批准号：
9893922
负责人：
Long-Jun Wu
金额：
$ 39.28万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2024-02-29
项目状态：
已结题

项目摘要

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.

总结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发作中提供有益的功能。在这次更新中，我们将进一步研究小胶质细胞在体内癫痫脑中的活动，并将联合收割机的细胞和功能结合起来，在实验性小鼠癫痫发作模型中进行电生理和行为研究。我们我们将从最初的资助周期中扩展我们的发现，以进一步表征小胶质细胞在脑中的活动。癫痫发作后的大脑，并提供进一步的证据，小胶质细胞神经保护在急性海人酸（KA）诱导的癫痫发作期。此外，我们将研究小胶质细胞在脑中的作用使用小胶质细胞消融和化学发生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。将沿着以下内容检验此假设具体目标：在目的1中，我们将研究的动力学和功能的小胶质细胞过程袋的压迫诱导。在目标2中，我们将确定小胶质细胞对癫痫发生的贡献。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，这笔赠款将扩大初步资助的结果，以阐明有益的作用，此外，这种更新将突出有害的小胶质细胞在促进脑胶质细胞诱导的神经发生、神经元发芽、神经元再生和神经元再生中的作用兴奋性和自发性癫痫发作的慢性阶段。这项研究不仅可以改善我们对小胶质细胞癫痫发生机制的理解，也表明小胶质细胞是治疗癫痫和癫痫的潜在治疗靶点。