Astrocytes and temporal lobe epilepsy

描述(申请人提供)：颞叶癫痫(TLE)是一种破坏性的癫痫，很难用抗癫痫药物控制，通常在最初对中枢神经系统的侮辱后发生。为了更好地了解癫痫的发生过程和开发治疗TLE的创新方法，已经建立了显示这种癫痫障碍的一些特征的动物模型：作为对中枢神经系统的初始侮辱的癫痫持续状态(SE)期，在此期间不发生癫痫发作的可变潜伏期，以及最终发展为源于颞叶的反复自发性癫痫发作。几十年来对这类模型的研究已经产生了大量关于海马区(HC)神经元在TLE中的作用的知识。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，我们实验室利用红藻氨酸(KA)模型对这种“反应性”星形胶质细胞进行了研究。在这个常用的TLE动物模型中，我们有了一个新的发现，星形胶质细胞显著增加了离子亲红素受体亚单位KA1的表达。我们假设，这些新表达的海人藻酸受体的激活诱导兴奋性神经胶质传递，使附近的CA1锥体细胞去极化。这种在海马区的兴奋性神经胶质传递可能对同步化和癫痫的产生有重要的影响，这个探索性的提议将执行两个特定的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是否导致星形胶质细胞上海人酸受体表达的长期增加。《特定目的2》将利用全细胞膜片钳技术，确定表达在星形胶质细胞上的海人藻酸受体的激活是否诱导了胶质传递，从而激活了KA诱导的SE动物脑片中CA1锥体细胞的兴奋性氨基酸受体。预计对星形胶质细胞在TLE中作用的了解将为这种经常耐药的癫痫障碍的治疗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，这项拟议的研究将评估癫痫动物模型中神经胶质细胞中一种特定类型的兴奋性氨基酸受体的变化。预计这项工作将揭示癫痫治疗的新的潜在治疗靶点。

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.