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：
10396346
负责人：
DEVIN K BINDER
金额：
$ 4.06万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396346
关键词：
Acute Affect Agonist Astrocytes Atrophic Autopsy Axon Behavioral Brain C57BL/6 Mouse Chronic Clinical Cognition Cognitive deficits Communities Corpus striatum structure Coupled Cuprizone Custom Demyelinations Development Diet Disease Progression Electrophysiology (science)Epilepsy Epileptogenesis Estrogen Receptor beta Foundations Future Gene Expression Gene Proteins Glutamates Goals Golgi Apparatus Hippocampus (Brain)Homeostasis Immunohistochemistry Impaired cognition Impairment Individual Interneurons Knowledge Lead Learning Lesion Ligands Long-Term Potentiation Measures Memory Memory Disorders Memory impairment Mission Modeling Molecular Multiple Sclerosis Mus National Institute of Neurological Disorders and Stroke Neurologic Neurons Neurosciences Neurotransmitters Parvalbumins Pathology Phase Population Primary Progressive Multiple Sclerosis Process Proteins Public Health Publishing Pyramidal Cells Research Research Project Grants Seizures Slice Stains Synapses Synaptic Transmission Testing Therapeutic Time Transgenic Organisms United States National Institutes of Health Water Western Blotting chronic demyelination effective therapy epidemiology study excitotoxicity gray matter hippocampal atrophy improved indexing inhibitory neuron insight memory recall mouse model multiple sclerosis patient myelination nano-string nervous system disorder neuroimaging novel object recognition patch clamp receptor translational study uptake

项目摘要

Cognitive impairment occurs and is more prevalent during primary progressive MS[1]. While MS clinical presentation is protean, epidemiological studies have revealed that MS patients are three to six times more likely to develop epileptic seizures than the population at large. Excitotoxic neuronal damage in the hippocampus (and other regions) is thought to be one of the causes for cognitive deficits in nearly 50% of multiple sclerosis (MS) patients and could be due glutamate dyshomeostasis. Glutamate is a major excitatory neurotransmitter in the mammalian CNS. Our recent published results have shown i) a decrease in inhibitory parvalbumin neurons of chronic cuprizone-diet fed demyelinating mice (Lapato et al., 2016) and in the hippocampus of MS patients with seizures (Lapato et al., 2020); ii) astrocyte glutamate uptake and water homeostasis are dysregulated in the hippocampus of MS patients with seizures (Lapato et al., 2020)[4]. The objective of this application is to understand how demyelination-induced loss of inhibitory neurons impacts hippocampal changes that lead to learning and memory deficits. We hypothesize that chronic demyelination induces decrease in hippocampus PV neurons and indices substantial changes in synaptic transmission involved in learning and memory. In aim 1: we will determine chronic cuprizone diet-demyelination induced changes in long term potentiation by electrophysiology in brain slices. In aim 2, we will examine synaptic changes during chronic demyelination in the CA1 and striatum radiatum regions of the hippocampus. In aim 3, we will assess chronic demyelination induced changes in learning and memory. We anticipate that this research will be transformative, as we will introduce to the research community a functional and molecular mechanism for memory disorder due to demyelination.

认知障碍在原发性进行性多发性硬化症期间发生且更为普遍[1]。而 MS 临床表现形式千变万化，流行病学研究表明，多发性硬化症患者的可能性是多发性硬化症患者的三到六倍比一般人群更容易发生癫痫发作。海马区的兴奋性毒性神经元损伤（和其他地区）被认为是近 50% 多发性硬化症 (MS) 患者认知缺陷的原因之一患者，可能是由于谷氨酸稳态失调所致。谷氨酸是一种主要的兴奋性神经递质哺乳动物中枢神经系统。我们最近发表的结果表明 i) 抑制性小白蛋白神经元减少慢性铜宗饮食喂养的脱髓鞘小鼠（Lapato et al., 2016）和多发性硬化症患者的海马癫痫发作（Lapato 等人，2020）； ii) 星形胶质细胞谷氨酸摄取和水稳态失调癫痫发作的多发性硬化症患者的海马体（Lapato 等人，2020）[4]。该应用程序的目的是了解脱髓鞘引起的抑制性神经元丧失如何影响海马体变化，从而导致学习和记忆缺陷。我们假设慢性脱髓鞘导致海马 PV 减少神经元并指数参与学习和记忆的突触传递的显着变化。目标 1：我们将确定慢性铜宗饮食脱髓鞘引起的长期增强的变化脑切片中的电生理学。在目标 2 中，我们将检查慢性脱髓鞘过程中的突触变化海马体的 CA1 和放射状纹状体区域。在目标 3 中，我们将评估诱发的慢性脱髓鞘学习和记忆的变化。我们预计这项研究将具有变革性，因为我们将介绍研究界发现了脱髓鞘引起的记忆障碍的功能和分子机制。