The Role of Microglia in Epilepsy

描述（由申请人提供）：癫痫是一种神经系统疾病，可表现为患者无法控制的癫痫发作。小胶质细胞对中枢神经系统的破坏非常敏感。由于癫痫的特征在于神经元过度活动，其根源在于过量的谷氨酸释放和离子失衡，因此可以想象，小胶质细胞可以在病理过程中发挥减少神经元功能障碍和促进神经元健康的功能。在我们的初步研究中，我们已经发现，在急性脑切片中谷氨酸水平升高期间，小胶质细胞通过强大的过程延伸做出反应，从而增加与神经元的接触。此外，在三种不同的癫痫样活动模型中，小胶质细胞过程集中在神经元树突上，小胶质细胞消融降低了行为癫痫发作评分。根据我们的初步结果，我们假设，在谷氨酸水平增加的神经元过度活跃的信号，诱导其过程中的扩展小胶质细胞。此外，在过度活跃的神经元活动期间，小胶质细胞过程集中于神经元元件，结果下调这种过度活跃，这在限制行为性癫痫发作结果和促进神经元存活中是关键的。我们现在将沿着以下具体目标来检验这个假设。在目标1中，我们将确定背后的谷氨酸诱导的小胶质细胞的过程延伸阐明神经元受体启动和释放的化学引诱剂介导的过程延伸信号的潜在机制。在目标2中，我们将确定小胶质细胞过程焦点的目标以及介导急性脑切片中癫痫样活动的三种模型中的反应的化学引诱物。在目标3中，我们将在急性脑切片中的观察扩展到活体脑，并通过小胶质细胞消融和独特的小胶质细胞P2 Y12受体的遗传缺失来确定小胶质细胞在癫痫诱导的癫痫发作行为和神经元细胞死亡中的作用。这些研究首次探讨了急性癫痫期间小胶质细胞的动力学。他们将增加我们对癫痫活动期间小胶质细胞-神经元相互作用的机制以及小胶质细胞在癫痫中的神经保护潜力的理解。此外，这些研究的结果将提供新的数据，可以为开发治疗癫痫疾病的新疗法提供信息。

DESCRIPTION (provided by applicant): Epilepsy represents a neurological disorder that can manifest in uncontrolled seizures in patients. Microglia are exquisitely sensitive to disruptions i the central nervous system. Since epilepsy is characterized by neuronal hyperactivity activity rooted in excessive glutamate release and ionic imbalance, it is conceivable that microglia may perform functions to reduce neuronal dysfunction and promote neuronal health during the pathology. In our preliminary studies, we have found that microglia respond by robust process extension making increasing contact with neurons during elevated glutamate levels in acute brain slices. Moreover, in three different models of epileptiform activity, microglial processes focus on neuronal dendrites and microglial ablation reduces behavioral seizure scores. Based on our preliminary results, we hypothesize that during increased glutamate levels hyperactive neurons signal to microglia inducing their process extension. Additionally, during hyperactive neuronal activity, microglial processes focus on neuronal elements with a consequence to downregulate such hyperactivity which is critical in limiting behavioral seizure outcome and promoting neuronal survival. We will now test this hypothesis along with the following specific aims. In Aim 1, we will determine the underlying mechanisms behind glutamate-induced microglial process extension elucidating the neuronal receptors initiating and the released chemoattractants mediating the process extension signal. In Aim 2, we will determine the targets of microglial process focus as well as the chemoattractants mediating the response in three models of epileptiform activity in acute brain slices. In Aim 3, we will extend our observations in acute brain slices to in vivo live brain and determine the role of microglia in epilepsy-induced seizure behaviors and neuronal cell death by microglial ablation and genetic deletion of the unique microglial P2Y12 receptor. These studies are the first to investigate the microglial dynamics during acute epilepsy. They will increase our understanding of the mechanisms underlying microglial-neuronal interactions during epileptic activity and the neuroprotective potential of microglia in epilepsy. In addition, the outcome of these studies will provide new data that could inform the development of novel therapies in the treatment of epileptic disorders.