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）是一种难以用抗惊厥药物控制的破坏性癫痫发作疾病，通常在CNS初始损伤后发生。为了更好地了解癫痫发生的过程并开发用于管理TLE的创新治疗方法，已经开发了表现出这种癫痫发作障碍的一些特征的动物模型：癫痫持续状态（SE）期，其作为对CNS的初始损伤，可变的潜伏期，在此期间不发生癫痫发作，以及复发的最终发展，源于颞叶的自发性癫痫几十年的研究在这样的模型已经产生了大量的知识海马（HC）中的神经元在TLE中的作用。然而，目前对星形胶质细胞在TLE中的功能作用知之甚少：星形胶质细胞是大脑中的另一种主要细胞类型。最近，我们的实验室利用海人酸（KA）模型的SE调查这种“反应性”星形胶质细胞。在这个常用的TLE动物模型中，我们发现星形胶质细胞显著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诱导兴奋性胶质传递，使附近的CA1锥体细胞去极化。这种兴奋性gliotransmission在海马体可能有显着的影响，同步和癫痫发作的产生，这个探索性的建议将执行两个具体的目标，以测试这一整体假设。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诱导胶质传递，其激活KA诱导SE后动物脑切片中CA 1锥体细胞中的兴奋性氨基酸受体。预期星形胶质细胞在TLE中的作用的增加的理解将提供用于治疗这种频繁的治疗抗性癫痫发作病症的创新分子靶点。公共卫生相关性：越来越多的证据表明，非神经胶质细胞可能有助于癫痫发作和癫痫。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。