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：
9590724
负责人：
Long-Jun Wu
金额：
$ 25.3万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-11-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9590724
关键词：
Ablation Acute Address Astrocytes Behavior Behavioral Brain Brain Diseases Cells Characteristics Chemotactic Factors Chronic Communication Complement Data Dendrites Dendritic Spines Development Disease Electrophysiology (science)Elements Epilepsy Exhibits Genetic Glutamate Receptor Glutamates Health Hippocampus (Brain)Human Hyperactive behavior Immune Injection of therapeutic agent Kainic Acid Mediating Microglia Microscopy Modeling Morphology NMDA receptor antagonist Neuraxis Neuronal Dysfunction Neurons Outcome Outcome Study Pathology Patients Plant Roots Process Research Resolution Role Seizures Signal Transduction Slice Techniques Testing Therapeutic Time base behavior test experimental study extracellular in vivo nervous system disorder neuron loss neuronal survival novel strategies novel therapeutics public health relevance receptor response social therapy development two-photon

项目摘要

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.

描述（由申请人提供）：癫痫代表一种神经系统疾病，可以表现在患者不受控制的癫痫发作中。小胶质细胞对中枢神经系统的干扰非常敏感。由于癫痫的特征是神经元多动活性根源于谷氨酸过度释放和离子不平衡，因此可以想象，小胶质细胞可以发挥功能来降低神经元功能障碍并在病理过程中促进神经元健康。在我们的初步研究中，我们发现小胶质细胞通过稳健的过程扩展做出反应，从而使急性脑切片中谷氨酸水平升高的神经元的接触增加。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于神经元树突和小胶质细胞消融可降低行为癫痫发作得分。基于我们的初步结果，我们假设在增加谷氨酸水平的过程中，多动神经元信号对小胶质细胞诱导其过程扩展。此外，在多动神经元活性期间，小胶质细胞过程集中在神经元元素上，其结果下调了这种多动症，这对于限制行为癫痫发作和促进神经元存活至关重要。现在，我们将测试该假设以及以下特定目标。在AIM 1中，我们将确定谷氨酸诱导的小胶质细胞过程伸展背后阐明神经元受体的启动和介导过程扩展信号的释放的趋化剂。在AIM 2中，我们将确定小胶质过程焦点的靶标以及在急性脑切片中三种癫痫样活性模型中介导的反应的化学吸引物。在AIM 3中，我们将将急性脑切片中的观察结果扩展到体内活体大脑，并确定小胶质细胞在癫痫引起的癫痫发作行为中的作用和通过小胶质细胞消融和独特的小胶质细胞P2Y12受体的遗传缺失和遗传缺失。这些研究是第一个研究急性癫痫期间小胶质细胞动力学的研究。他们将提高我们对癫痫活性中小胶质细胞 - 神经元相互作用的机制的理解以及小胶质细胞在癫痫中的神经保护潜力。此外，这些研究的结果将提供新的数据，可以为癫痫疾病疗法的新疗法发展提供信息。