EVOLUTION OF ALTERED INHIBITION IN EPILEPSY

癫痫抑制改变的演变

• 批准号: 6363912
• 负责人: PATRICK S MANGAN
• 金额: $ 10.99万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6363912
• 关键词: GABA receptor; brain electrical activity; epilepsy; gamma aminobutyrate; gene induction /repression; hippocampus; laboratory rat; microelectrodes; neural inhibition; neurons; neuropharmacology; voltage /patch clamp

DESCRIPTION: Temporal lobe epilepsy (TLE), the most common form of partial epilepsy, remains the cause of seizures most resistant to treatment. Understanding the pathophysiological factors inducing chronic seizure development is a necessary prerequisite to devising more effective therapies. Human TLE is marked by major pathology of the mesial temporal lobe, particularly the hippocampal formation and parahippocampal structures. A mesial temporal lobe epilepsy syndrome has been described which is often typified by a nervous system insult followed by a seizure-free interval and eventual onset of chronic epilepsy. It is generally agreed that an increased propensity for epileptiform activity arises from a disequilibrium between neuronal excitation and inhibition, particularly that mediated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). A fundamental question which remains unanswered is the nature of the process occurring during the post-status epilepticus, seizure-free interval which may reduce GABAergic inhibition and lead to an increased propensity for epileptiform activity. This proposal examines the evolution of impairments to GABAA receptor-mediated inhibition during the period preceding the onset of spontaneous seizures using an animal model of chronic epilepsy. Three hypotheses are considered: 1. The changes in GABAA receptor-mediated inhibition in hippocampal region CA1 appear incrementally following status epilepticus and precede the appearance of chronic epilepsy. 2. Alterations in the pharmacology of the GABAA receptor evolve and are complete before the onset of spontaneous seizures. 3. The properties of spontaneous inhibitory postsynaptic currents alter between the induction of status epilepticus and the onset of spontaneous seizures. The information gained in these studies will better define development of GABAergic deficiencies preceding seizures and will aid in the development of new anti-epileptogenic therapies.

描述：颞叶癫痫（TLE），最常见的部分性癫痫。 癫痫，仍然是癫痫发作的原因最难治疗。 慢性癫痫的病理生理因素 发展是制定更有效的 治疗 人类颞叶癫痫的特点是颞叶内侧的主要病理 叶，特别是海马结构和海马旁结构。 人们已经描述了一种内侧颞叶癫痫综合征，这种综合征通常是 典型表现为神经系统损伤，随后为无损伤间隔， 最终导致慢性癫痫发作。 人们普遍认为， 癫痫样活动倾向的增加是由于不平衡 在神经元兴奋和抑制之间，特别是由 抑制性神经递质γ-氨基丁酸（GABA）。 一 一个尚未回答的根本问题是这一过程的性质 发生在癫痫持续状态后的无癫痫间期， 可能减少GABA能抑制，并导致增加的倾向， 癫痫样活动 本提案审查了损害的演变 GABAA受体介导的抑制在发病前的时期 自发性癫痫发作的研究。 三 假设被认为：1. GABAA受体介导的 海马CA 1区抑制在以下状态下逐渐出现 癫痫发作期和慢性癫痫出现之前。 2. 改变 在GABAA受体的药理学进化和完成之前， 自发性癫痫发作 3. 自发抑制的性质 突触后电流在癫痫持续状态的诱导和 自发性癫痫发作 从这些研究中获得的信息 将更好地定义癫痫发作前GABA能缺乏症的发展 并将有助于开发新的抗癫痫治疗方法。