Role of Perineuronal Nets in Epilepsy

神经周围网在癫痫中的作用

• 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
• 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

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/摘要 全世界约有5000万人患有癫痫，这是一种以反复发作， 无诱因的癫痫发作，表现为行为改变和异常放电的组合， 大脑中的神经元群体。癫痫发作是由兴奋-抑制（E-I）平衡受损引起的。 增强抑制性GABA能功能是一种常见的药理学策略。毫不奇怪的是， 已经对皮层和海马中的GABA能中间神经元进行了充分的研究，并且它们在抑制神经元的活动中的作用已经被证实。 来自这些结构的兴奋性输出是很好建立的。GABA能中间神经元倾向于快速发放细胞 (up到800 Hz！），通过每个动作电位的高水平活动来补偿它们的数量少 导致末端释放GABA大多数快速放电的神经元都被一层 高尔基在120多年前称之为神经元周网（PNNs）的致密细胞外基质。这些是 由糖胺聚糖组成，由蛋白质超家族形成的带负电荷的糖蛋白， 覆盖细胞索马、近端树突和轴突起始段。他们的作用不为人所知，但据信有助于 在细胞分化、神经保护和皮质可塑性方面。在上一个研究肿瘤的拨款周期里- 与癫痫相关，我们有了一个意想不到的发现，表明PNNs改变了神经元膜 电容，使它们能够以超生理速率发射。特别地，从细胞中释放的蛋白水解酶 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可能是获得性癫痫的更普遍的靶点， 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 完整性及其在获得性癫痫的不同小鼠模型中更广泛的癫痫发生中的作用， 癫痫病人的组织。我们假设PNN定义了突触附近星形胶质细胞的位置， 帮助离子和神经递质的吸收;从反应性星形胶质细胞释放基质降解酶 破坏PNN，从而减慢它们的射击速度。这些变化可能导致癫痫。这些研究 概念新颖，并可能提出一种完全不同的癫痫治疗方法，即靶向 蛋白水解酶来改善这种疾病。