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

基本信息

批准号：
10339389
负责人：
DEVIN K BINDER
金额：
$ 33.13万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
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/10339389
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

项目摘要

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.

项目概要多发性硬化症 (MS) 患者患癫痫的可能性是其他患者的三到六倍人口。然而，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未知。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行性变。本申请的目的是定义脱髓鞘本身的过程引起细胞、分子和回路的变化，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、小清蛋白 (PV)+ 中间神经元丧失以及神经元功能障碍相关。星形胶质细胞代谢/运输。这个假设是基于我们最近发表的工作，证明了显着的喂食 0.2% 铜宗饮食 (CPZ) 的小鼠脑电图 (EEG) 和自发性癫痫发作的变化 9-12周的时间；随后的免疫组织化学显示海马中 PV+ 神经元的丢失 CA1 亚区以及广泛的神经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进行比较。拟议研究的基本原理是详细的时空监测在 CPZ 治疗的小鼠中使用多电极阵列 (MEA) 检测脑电图活动将能够识别位点以及慢性脱髓鞘过程中癫痫发作开始的时间，这将指导兴奋性/抑制性的探测通过免疫组织化学和电生理技术进行历史神经传递和细胞/分子变化尼克斯。根据新的初步数据，将通过追求三个具体目标来检验中心假设：1）定义慢性脱髓鞘相关癫痫发作的空间和时间发生； 2）评估角色 GABA 能神经元，尤其是 PV 神经元在慢性脱髓鞘诱导的神经细胞生成中的作用苏雷斯； 3）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患者人体组织的直接比较伴有或不伴有癫痫发作的多发性硬化症将阐明与脱髓鞘相关的细胞和分子变化导致癫痫易感性。拟议的研究意义重大，因为它将推进基础研究了解大脑中神经胶质-神经元相互作用的知识，同时提供新的、合理的策略和治疗用于预防和治疗多发性硬化症相关的癫痫发作。