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：
10771375
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
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/10771375
关键词：
Abate Ablation Acceleration 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 Human Human Pathology Immunohistochemistry Impairment Interneurons Knowledge Lesion Leukocytes Link Location Mediator 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 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.

项目摘要与其他的硬化症患者相比，多发性硬化症患者的发生癫痫的可能性高三到六倍人口。但是，尽管该组患有更大的发病率，但MS相关性癫痫发作的病理生理学是未知的。我们的长期目标是确定将脱髓鞘与神经元过渡性联系起来的机制和神经变性。此应用程序的目的是定义脱髓鞘本身的过程导致细胞，分子和电路变化，增加神经元兴奋性。我们的中心假设是脱髓鞘与兴奋性升高，白蛋白（PV）+中间神经元的丧失以及功能障碍星形胶质细胞代谢/运输。该假设是基于我们最近发表的作品证明了明显的供电的脑电图（EEG）和自发癫痫发作的变化喂养0.2％cuprizone Diet（CPZ） 9-12周的时间；随后的免疫组织化学显示海马中PV+神经元的丧失 CA1子区域以及广泛的神经胶质变化以及星形细胞水通道蛋白4（AQP4）表达的变化按照正常饮食的小鼠折磨。拟议的研究的理由是，详细的时空moni- 用多电极阵列（MEA）在CPZ处理的小鼠中锻炼EEG活性将允许识别该基因座以及慢性脱髓鞘期间癫痫发作的时间，这将指导兴奋/抑制作用的探测免疫组织化学和电生理技术的迭代神经传递和细胞/分子变化 niques。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）定义慢性脱髓鞘相关性癫痫发作的空间和时间产生； 2）评估 GABA能神经元，强调PV神经元在慢性脱髓鞘引起的sei-sei- Zures; 3）评估星形胶质细胞在慢性脱髓鞘过程中的区域癫痫敏感性中的作用。小说电生理和转基因方法与患者的人体组织直接比较使用和没有癫痫发作的MS将阐明与脱髓鞘相关的细胞和分子变化，这些变化导致癫痫发作的敏感性。拟议的研究很重要，因为它将提高基本在提供新的和理性的策略和治疗的同时，了解大脑中神经神经神经元相互作用的知识用于预防和治疗与MS相关的癫痫发作。