Demyelination is coupled to neuronal hyperexcitability leading to seizures

项目总结 多发性硬化症(MS)患者患癫痫的可能性是其他患者的三到六倍 人口。然而，尽管这类人群的发病率更高，但MS相关癫痫的病理生理学 是未知的。我们的长期目标是确定脱髓鞘与神经元过度兴奋之间的联系机制。 和神经退化。本申请的目标是定义脱髓鞘本身的过程 导致细胞、分子和电路的变化，增加神经元的兴奋性。我们的中心假设是 脱髓鞘与兴奋性升高、小白蛋白(PV)+中间神经元丢失以及 星形胶质细胞代谢/运输。这一假设是基于我们最近发表的工作，证明了有标记的 饲喂0.2%铜酮饲料的小鼠脑电和自发性癫痫发作的变化 9-12周；随后的免疫组织化学显示海马区PV+神经元丢失 CA1亚区、广泛的胶质增生和星形细胞水通道蛋白-4(AQP4)表达的变化。 与正常饮食的小鼠相比。这项拟议研究的基本原理是，详细的时空单因素-- 用多电极阵列(MEA)监测CPZ治疗的小鼠的脑电活动将有助于确定该基因座 和慢性脱髓鞘期间癫痫发作的启动时间，这将指导兴奋性/抑制性- 免疫组织化学和电生理技术检测神经传递和细胞/分子变化 小甜饼。基于新的初步数据，将通过追求三个具体目标来检验中心假设：1) 确定慢性脱髓鞘相关癫痫发作的空间和时间发生；2)评估 GABA能神经元在慢性脱髓鞘诱导的SEI中的作用 3)评估星形胶质细胞在慢性脱髓鞘过程中对局部癫痫易感性的作用。小说 电生理和转基因方法以及与患者人体组织的直接比较 伴有和不伴有癫痫的多发性硬化症将阐明脱髓鞘相关的细胞和分子变化， 导致癫痫易感性。这项拟议的研究意义重大，因为它将推动基础性研究 在提供新的合理的策略和治疗的同时，了解大脑中神经胶质细胞和神经元的相互作用 用于预防和治疗多发性硬化症相关癫痫。

PROJECT SUMMARY Multiple sclerosis (MS) patients are three to six times more likely to develop epilepsy compared to the rest of the population. However, while this groups suffers greater morbidity, the pathophysiology of MS-associated seizures is unknown. Our long-term goal is to identify mechanisms linking demyelination to neuronal hyperexcitability and neurodegeneration. The objective in this application is to define the processes by which demyelination itself causes cellular, molecular and circuit changes increasing neuronal excitability. Our central hypothesis is that demyelination is coupled to elevated excitability, loss of parvalbumin (PV)+ interneurons, and dysfunction of astrocyte metabolism/transport. This hypothesis is based on our recently published work demonstrating marked changes in electroencephalography (EEG) and spontaneous seizures in mice fed 0.2% cuprizone diet (CPZ) over a period of 9-12 weeks; and subsequent immunohistochemistry revealed loss of PV+ neurons in the hippocampal CA1 subregion together with widespread gliosis and changes in astrocytic aquaporin-4 (AQP4) expression com- pared to mice on a normal diet. The rationale for the proposed research is that detailed spatiotemporal moni- toring of EEG activity with multielectrode arrays (MEA) in CPZ-treated mice will allow identification of the locus and timing of seizure initiation during chronic demyelination, and this will direct the probe of excitatory/inhib- itory neurotransmission and cellular/molecular changes by immunohistochemical and electrophysiological tech- niques. Based on new preliminary data, the central hypothesis will be tested by pursuing three specific aims: 1) Define the spatial and temporal generation of chronic demyelination-associated seizures; 2) Evaluate the role of GABAergic neurons with an emphasis of PV neurons in the generation of chronic demyelination-induced sei- zures; 3) Evaluate the role of astrocytes in regional seizure susceptibility during chronic demyelination. Novel electrophysiological and transgenic approaches together with direct comparison to human tissue from patients with MS with and without seizures will elucidate demyelination-associated cellular and molecular changes that lead to seizure susceptibility. The proposed research is significant, because it will advance fundamental knowledge of glial-neuronal interactions in the brain while providing new and rational strategies and treatments for prevention and treatment of MS-associated seizures.