Role of Perineuronal Nets in Epilepsy

神经周围网在癫痫中的作用

基本信息

批准号：
10404250
负责人：
HARALD W SONTHEIMER
金额：
$ 31.2万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2021-05-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10404250
关键词：
Action Potentials Acute Affect Agglutinins Amino Acids Astrocytes Axon Behavior Binding Biophysics Brain Buffers Cell Differentiation process Cells Charge Chronic Clinical Dendrites Development Digestion Disease Electric Capacitance Electrodes Electrostatics Ensure Enzyme Reactivation Enzymes Epilepsy Epileptogenesis Equilibrium Excitatory Synapse Extracellular Matrix Fire - disasters Frequencies Genetic Glycoproteins Glycosaminoglycans Golgi Apparatus Grant Health Hippocampus (Brain)Homeostasis Hyaluronidase Immunohistochemistry Impairment Infection Injury Interneurons Ions Label Lead Lesion Matrix Metalloproteinases Mediating Membrane Modeling Mus Myelin Nerve Degeneration Neurons Output Parvalbumins Patients Peptide Hydrolases Pharmaceutical Preparations Pharmacology Physiological Population Process Property Proteins Proteolysis Role Seizures Speed Stains Stroke Structure Sulfate Synapses Syndrome Therapeutic Tissues Vertebral column Wisteria acquired epilepsy clinically relevant extracellular gamma-Aminobutyric Acid human tissue inhibitory neuron mouse model nervous system disorder neuronal cell body neurotransmission neurotransmitter release novel novel strategies patch clamp postsynaptic prevent preventable epilepsy receptor relating to nervous system sugar synaptic function therapeutic target tumor uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Approximately 50 million people worldwide live with epilepsy, a syndrome characterized by repeated, unprovoked seizures that manifest with a combination of altered behavior and abnormal electric discharges of populations of neurons in the brain. Seizures result from impairment of excitatory-inhibitory (E-I) balance. Enhancement of inhibitory GABAergic function is a common pharmacological strategy. Not surprisingly, GABAergic interneurons in the cortex and hippocampus have been well studied, and their role in dampening excitatory output from these structures is well established. GABAergic interneurons tend to be fast-spiking cells (up to 800Hz!), which compensate for their small number by a high level of activity with each action potential causing GABA release from their terminals. A majority of these fast-spiking neurons are surrounded by a layer of dense extracellular matrix that Golgi termed perineuronal nets (PNNs) over 120 years ago. These are composed of glycosaminoglycanes, negatively charged glycoproteins formed from a superfamily of proteins that cover the cell soma, proximal dendrites and axon initial segment. Their role is not well known but believed to aid in cell differentiation, neural protection and cortical plasticity. During the last grant cycle studying tumor- associated epilepsy, we made an unexpected discovery suggesting that PNNs alter the neuronal membrane capacitance, allowing them to fire at supra-physiological rates. Specially, proteolytic enzymes released from the tumor digest PNNs, thereby increasing membrane capacitance and slowing the firing rates of inhibitory neurons, leading to seizures. We now hypothesize that PNNs may be more generally the target of acquired epilepsy, where proteolysis of extracellular matrix and tissue remodeling are common. Hence, we propose to study PNN integrity and its role in epileptogenesis more broadly across different mouse models of acquired epilepsy and in tissues from epilepsy patients. We hypothesize that PNNs define the placement of astrocytes near synapses to aid uptake of ions and neurotransmitters; that release of matrix-degrading enzymes from reactive astrocytes destroy PNNs, thereby slowing their firing rate. Together these changes may lead to epilepsy. These studies are conceptually novel and may suggest a completely different treatment approach to epilepsy, namely targeting proteolytic enzymes to ameliorate this disease.

项目概要/摘要全球约有 5000 万人患有癫痫症，这是一种以反复发作、无端癫痫发作，表现为行为改变和异常放电相结合大脑中的神经元群。癫痫发作是由于兴奋抑制 (E-I) 平衡受损所致。增强抑制性 GABA 功能是一种常见的药理学策略。毫不奇怪，皮层和海马体中的 GABA 能中间神经元已得到充分研究，它们在抑制中的作用这些结构的兴奋性输出已得到充分证实。 GABA能中间神经元往往是快速放电细胞（高达 800Hz！），通过每个动作电位的高水平活动来补偿其数量较少导致 GABA 从终端释放。大多数这些快速尖峰神经元被一层包围 120 多年前，高尔基将其称为神经周围网 (PNN)。这些都是由糖胺聚糖组成，糖胺聚糖是由蛋白质超家族形成的带负电荷的糖蛋白，覆盖细胞体、近端树突和轴突起始段。他们的作用并不为人所知，但据信可以提供帮助细胞分化、神经保护和皮质可塑性。在研究肿瘤的最后一个拨款周期中与癫痫相关，我们有一个意想不到的发现，表明 PNN 改变了神经元膜电容，使它们能够以超生理速率发射。特别是，从细胞中释放出的蛋白水解酶肿瘤消化 PNN，从而增加膜电容并减慢抑制性神经元的放电速率，导致癫痫发作。我们现在假设 PNN 可能更普遍地是获得性癫痫的目标，其中细胞外基质的蛋白水解和组织重塑是常见的。因此，我们建议研究PNN 完整性及其在不同小鼠获得性癫痫模型中更广泛的癫痫发生中的作用来自癫痫患者的组织。我们假设 PNN 定义了星形胶质细胞在突触附近的位置帮助吸收离子和神经递质；从反应性星形胶质细胞中释放基质降解酶摧毁 PNN，从而降低其发射速度。这些变化共同可能导致癫痫。这些研究是概念新颖，可能提出一种完全不同的癫痫治疗方法，即靶向治疗蛋白水解酶可以改善这种疾病。