The Role of Microglia in Epilepsy

描述(由申请人提供)：癫痫是一种神经疾病，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。由于癫痫的特点是源于谷氨酸过度释放和离子失衡的神经元过度活动，可以想象小胶质细胞在病理过程中可能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，我们发现小胶质细胞通过强大的突起延伸做出反应，在急性脑片中谷氨酸水平升高时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，小胶质细胞突起集中在神经元树突上，小胶质细胞消融术降低了行为发作评分。根据我们的初步结果，我们假设在谷氨酸水平升高期间，过度活跃的神经元向小胶质细胞发出信号，诱导其突起延长。此外，在过度活跃的神经元活动中，小胶质细胞突起集中在神经元元件上，从而下调这种过度活动，这在限制行为癫痫结局和促进神经元存活方面至关重要。我们现在将测试这一假设以及以下具体目标。在目标1中，我们将确定谷氨酸诱导的小胶质细胞突起延长的潜在机制，阐明神经元受体的启动和释放的趋化物质介导突起延长信号。在目标2中，我们将确定小胶质突起病灶的靶点以及在急性脑片癫痫样活动的三种模型中介导反应的化学诱导剂。在目标3中，我们将把我们在急性脑片上的观察扩展到活体脑内，并通过小胶质细胞消融和独特的小胶质细胞P2Y12受体的基因缺失来确定小胶质细胞在癫痫诱导的癫痫行为和神经细胞死亡中的作用。这些研究首次对急性癫痫期间的小胶质细胞动力学进行了研究。它们将增加我们对癫痫活动过程中小胶质细胞与神经元相互作用的潜在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，为癫痫疾病治疗的新疗法的开发提供信息。

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.