权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10516038
负责人：
HARALD W SONTHEIMER
金额：
$ 37.95万
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/10516038
关键词：
Action Potentials Acute Affect Agglutinins Amino Acids Astrocytes Axon Behavior Binding Biophysics Brain Buffers Cell Differentiation process Cells Charge Chronic Clinical Compensation Dendrites Development Digestion Disease Electric Capacitance Electrodes Electrostatics Ensure Enzymes Epilepsy Epileptogenesis Equilibrium Excitatory Synapse Extracellular Matrix Fire - disasters Frequencies Genetic Glycoproteins Glycosaminoglycans Golgi Apparatus Grant Health Hippocampus Homeostasis Hyaluronidase Immunohistochemistry Impairment Infection Injury Interneurons Ions Label Lesion Matrix Metalloproteinases Mediating Membrane Modeling Mus Myelin Nerve Degeneration Neurons Neurotransmitters Output Parvalbumins Patients Peptide Hydrolases Persons Pharmaceutical Preparations 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 neural neuronal cell body neurotransmission novel novel strategies patch clamp pharmacologic postsynaptic presynaptic prevent preventable epilepsy receptor 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.

项目总结/文摘