Role of Perineuronal Nets in Epilepsy

神经周围网在癫痫中的作用

• 批准号: 9973987
• 负责人: HARALD W SONTHEIMER
• 金额: $ 36.83万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973987
• 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; 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

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.

项目摘要/摘要 全球约有5000万人患有癫痫病，这是一种综合症，其特征是反复， 无端的癫痫发作与行为改变和异常电气排放相结合的无端癫痫发作 大脑中神经元的种群。癫痫发作是由兴奋性抑制（E-I）平衡损害引起的。 增强抑制性GABA能功能是一种常见的药理策略。毫不奇怪， 皮质和海马中的GABA能中间神经元已经很好地研究了，它们在抑郁症中的作用 这些结构的兴奋产量已经确定。 GABA能中间神经元往往是快速加速的细胞 （高达800Hz！），它通过每个动作潜力来补偿其少量活动 导致GABA从其终端释放。这些快速刺激的神经元中的大多数被一层包围 高尔基体在120年前称为周围神经元网（PNNS）的密集细胞外基质。这些都是 由糖胺聚糖组成，由蛋白质的超家族形成负电荷的糖蛋白 覆盖细胞体，近端树突和轴突初始段。他们的角色尚不为人所知，但被认为有助于 在细胞分化，神经保护和皮质可塑性中。在研究肿瘤的最后一个赠款周期中 相关的癫痫病，我们做出了一个意外的发现，表明PNN会改变神经元膜 电容，使他们能够以外生理率开火。特别是，蛋白水解酶从 肿瘤摘要PNN，从而增加膜电容并降低抑制性神经元的发射速率， 导致癫痫发作。现在，我们假设PNN可能是获得癫痫的目标，即 其中常见的细胞外基质和组织重塑的蛋白水解是常见的。因此，我们建议研究PNN 在获得性癫痫的不同小鼠模型和 癫痫患者的组织。我们假设PNNS定义了突触附近的星形胶质细胞的位置 有助于吸收离子和神经递质；从反应性星形胶质细胞中释放降解基质的酶 销毁PNN，从而减慢其射击速度。这些变化在一起可能会导致癫痫。这些研究是 从概念上进行新颖，可能建议采用完全不同的癫痫治疗方法 蛋白水解酶可以改善这种疾病。