EVOLUTION OF ALTERED INHIBITION IN EPILEPSY

癫痫抑制改变的演变

• 批准号: 6531077
• 负责人: PATRICK S MANGAN
• 金额: $ 11.45万
• 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 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6531077
• 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形式 癫痫，仍然是最难治疗的癫痫发作原因。 了解诱发慢性癫痫发作的病理生理因素 发展是制定更有效措施的必要前提 疗法。 人类 TLE 的特点是颞内侧的主要病理学 叶，特别是海马结构和海马旁结构。 内侧颞叶癫痫综合征已被描述，该综合征经常发生 其典型特征是神经系统受到损害，随后出现无癫痫发作间隔 最终出现慢性癫痫。 人们普遍认为， 癫痫样活动倾向增加是由不平衡引起的 神经元兴奋和抑制之间的关系，特别是由 抑制性神经递质γ-氨基丁酸（GABA）。 一个 仍未得到解答的基本问题是该过程的性质 发生在癫痫持续状态期间，无癫痫发作间隔 可能会减少 GABA 能抑制并导致增加倾向 癫痫样活动。 该提案研究了损伤的演变 发病前一段时间内 GABAA 受体介导的抑制作用 使用慢性癫痫动物模型研究自发性癫痫发作。 三 考虑假设： 1. GABAA 受体介导的变化 海马区 CA1 的抑制在以下状态下逐渐出现 癫痫并先于慢性癫痫的出现。 2. 变更 GABAA 受体的药理学在进化之前就已完成 自发性癫痫发作。 3. 自发抑制的特性 突触后电流在癫痫持续状态的诱导和 自发性癫痫发作。 这些研究中获得的信息 将更好地确定癫痫发作前 GABA 能缺陷的发展 并将有助于开发新的抗癫痫疗法。