Demyelination is coupled to neuronal hyperexcitability leading to seizures

脱髓鞘与神经元过度兴奋相关，导致癫痫发作

• 批准号: 10443908
• 负责人: DEVIN K BINDER
• 金额: $ 7.03万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443908
• 关键词: Abate; Ablation; Anatomy; Area; Astrocytes; Autopsy; Brain; Cells; Cessation of life; Chronic; Clinical Research; Connexins; Coupled; Coupling; Cuprizone; Data; Demyelinating Diseases; Demyelinations; Development; Diet; Disease; Dyes; Electroencephalography; Electrophysiology (science); Epilepsy; Epileptogenesis; Foundations; Functional disorder; Gap Junctions; Generations; Gliosis; Glutamates; Goals; Hippocampus (Brain); Human; Human Pathology; Immunohistochemistry; Impairment; Interneurons; Knowledge; Lead; Lesion; Leukocytes; Link; Location; Mediator of activation protein; Metabolic; Metabolism; Mission; Molecular; Monitor; Morbidity - disease rate; Morphology; Multiple Sclerosis; Mus; Nerve Degeneration; Neurons; Onset of illness; Outcome; Parvalbumins; Pathogenesis; Patients; Population; Predisposition; Prevention; Process; Proteins; Public Health; Publishing; Relapse; Reporter; Research; Rest; Role; Seizures; Signal Transduction; Specificity; Specimen; Stroke; Techniques; Testing; Time; Transgenic Organisms; Trauma; United States National Institutes of Health; Work; aquaporin 4; base; brain tissue; chronic demyelination; cognitive function; disability; human tissue; in vivo; insight; mouse model; multi-electrode arrays; multiple sclerosis patient; multiple sclerosis treatment; nervous system disorder; neuronal excitability; neurotransmission; novel; patient population; patient subsets; protein expression; reconstruction; spatiotemporal; translational impact; translational study

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.

项目摘要 多发性硬化症（MS）患者发生癫痫的可能性是其他患者的三到六倍。 人口然而，虽然这一群体的发病率较高，但MS相关癫痫发作的病理生理学 不明我们的长期目标是确定脱髓鞘与神经元过度兴奋的联系机制 和神经退化本申请的目的是确定脱髓鞘本身 引起细胞、分子和电路变化，增加神经元兴奋性。我们的核心假设是， 脱髓鞘与兴奋性升高、小白蛋白（PV）+中间神经元的损失和神经元的功能障碍有关。 星形胶质细胞代谢/转运。这一假设是基于我们最近发表的工作表明， 用0.2%铜唑酮（CPZ）饲料喂养小鼠， 9-12周;随后的免疫组织化学显示海马中PV+神经元丢失 CA 1亚区与广泛的胶质增生和星形胶质细胞水通道蛋白4（AQP 4）表达的变化， 给正常饮食的老鼠喂食。提出研究的理由是，详细的时空监测- 用多电极阵列（MEA）在CPZ处理的小鼠中存储EEG活动将允许识别位点 以及慢性脱髓鞘期间癫痫发作开始的时间，这将指导兴奋性/神经元b的探测， 通过免疫组织化学和电生理技术， 尼克。基于新的初步数据，中心假设将通过追求三个具体目标进行检验： 定义慢性脱髓鞘相关性癫痫发作的空间和时间生成; 2）评估 GABA能神经元与PV神经元在慢性脱髓鞘诱导的脊髓损伤中的作用 评估星形胶质细胞在慢性脱髓鞘过程中局部癫痫易感性中的作用。小说 电生理学和转基因方法以及与来自患者的人体组织的直接比较 MS伴或不伴癫痫发作的患者将阐明脱髓鞘相关的细胞和分子变化， 导致癫痫易感性。这项研究意义重大，因为它将推动基础研究的发展。 了解大脑中神经胶质-神经元相互作用，同时提供新的合理策略和治疗方法 用于预防和治疗MS相关癫痫发作。