Astrocytes and temporal lobe epilepsy

星形胶质细胞和颞叶癫痫

• 批准号: 7535112
• 负责人: Karen S Wilcox
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535112
• 关键词: Address; Agonist; Animal Model; Animals; Anticonvulsants; Astrocytes; Brain; Brain region; Calcium; Cells; Chronic; Corpus striatum structure; Development; Epilepsy; Epileptogenesis; Excitatory Amino Acid Receptors; Exhibits; Frequencies; Generations; Glutamates; Hippocampus (Brain); Human; Immunoblotting; Immunohistochemistry; Kainic Acid; Kainic Acid Receptors; Knowledge; Laboratories; Lead; Light; Maintenance; Medial; Modeling; Molecular Target; Neuroglia; Neurons; Numbers; Patch-Clamp Techniques; Pathologic; Phase; Preparation; Prevention; Probability; Process; Protein Array; Public Health; Pyramidal Cells; Rattus; Receptor Activation; Recurrence; Research; Role; Saline; Seizures; Signaling Molecule; Slice; Status Epilepticus; Synaptic plasticity; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Theoretical model; Therapeutic; Uncertainty; Week; Western Blotting; Work; cell type; direct application; entorhinal cortex; experience; improved; innovation; kainate; novel; patch clamp; receptor expression; research study; response; therapeutic target; therapy resistant

DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE), a devastating seizure disorder that is difficult to control with anticonvulsant drugs, often develops following an initial insult to the CNS. In order to better understand the process of epileptogenesis and to develop innovative therapeutic approaches for the management of TLE, animal models have been developed that exhibit some of the hallmarks of this seizure disorder: a period of status epilepticus (SE) which serves as the initial insult to the CNS, a variable latent period during which seizures do not occur, and the eventual development of recurrent, spontaneous seizures of temporal lobe origin. Decades of research in such models have generated a vast amount of knowledge on the role of neurons in the hippocampus (HC) in TLE. However very little is currently known about the functional role in TLE of astrocytes: the other major cell type within the brain. Recently our laboratory utilized the kainic acid (KA) model of SE to investigate such `reactive' astrocytes. In this commonly used animal model of TLE, we made the novel discovery that astrocytes dramatically increase the expression of the ionotropic kainate receptor subunit, KA1. We hypothesize that activation of these newly expressed kainate receptors induces excitatory gliotransmission that depolarizes nearby CA1 pyramidal cells. Such excitatory gliotransmission in the hippocampus may have significant implications with respect to synchronization and seizure generation and this exploratory proposal will perform two specific aims to test this overall hypothesis. Specific Aim 1 will use immunohistochemical and immunoblotting techniques to determine if KA- induced SE results in a long-term increase in expression of kainate receptors on astrocytes. Specific Aim 2 will use the whole cell patch clamp technique to determine if activation of kainate receptors expressed on astrocytes induces gliotransmission that activates excitatory amino acid receptors in CA1 pyramidal cells in brain slices obtained from animals following KA-induced SE. It is anticipated that an increased understanding of the role of astrocytes in TLE will provide innovative molecular targets for the treatment of this frequently therapy-resistant seizure disorder. PUBLIC HEALTH RELEVANCE: Increasing evidence suggests that non-neuronal glial cells may contribute to seizure generation and epilepsy. Therefore, the proposed research will evaluate changes in a specific type of excitatory amino acid receptor that occur in glial cells in an animal model of epilepsy. It is anticipated that this work will reveal new potential therapeutic targets for the treatment of epilepsy.

描述（由申请人提供）：颞叶癫痫（TLE）是一种破坏性癫痫病，很难用抗惊厥药物控制，通常在中枢神经系统最初受到损害后发生。为了更好地了解癫痫发生的过程并开发治疗 TLE 的创新治疗方法，我们开发了动物模型，这些模型表现出这种癫痫疾病的一些特征：一段癫痫持续状态 (SE) 时期，这是癫痫发作的初始阶段。对中枢神经系统的损害，不发生癫痫发作的可变潜伏期，以及最终发展为颞叶起源的复发性自发性癫痫发作。对此类模型的数十年研究已经产生了大量关于海马 (HC) 神经元在 TLE 中的作用的知识。然而，目前对于星形胶质细胞（大脑内的另一种主要细胞类型）在 TLE 中的功能作用知之甚少。最近，我们的实验室利用 SE 的红藻氨酸 (KA) 模型来研究这种“反应性”星形胶质细胞。在这种常用的 TLE 动物模型中，我们发现星形胶质细胞显着增加离子型红藻氨酸受体亚基 KA1 的表达。我们假设这些新表达的红藻氨酸受体的激活会诱导兴奋性神经胶质传递，使附近的 CA1 锥体细胞去极化。海马体中的这种兴奋性胶质细胞传递可能对同步和癫痫发作产生具有重大影响，并且该探索性提案将执行两个具体目标来检验这一总体假设。具体目标 1 将使用免疫组织化学和免疫印迹技术来确定 KA 诱导的 SE 是否会导致星形胶质细胞上红藻氨酸受体表达的长期增加。具体目标 2 将使用全细胞膜片钳技术来确定星形胶质细胞上表达的红藻氨酸受体的激活是否会诱导神经胶质传递，从而激活从 KA 诱导 SE 后获得的动物脑切片中的 CA1 锥体细胞中的兴奋性氨基酸受体。预计，对星形胶质细胞在 TLE 中的作用的进一步了解将为治疗这种经常难以治疗的癫痫病提供创新的分子靶点。公共卫生相关性：越来越多的证据表明，非神经元胶质细胞可能导致癫痫发作和癫痫。因此，拟议的研究将评估癫痫动物模型中神经胶质细胞中发生的特定类型兴奋性氨基酸受体的变化。预计这项工作将揭示治疗癫痫的新的潜在治疗靶点。