EVOLUTION OF ALTERED INHIBITION IN EPILEPSY

描述：颞叶癫痫(TLE)，最常见的部分 癫痫，仍然是癫痫发作最耐药的原因。 了解引起慢性癫痫发作的病理生理因素 发展是设计更有效的方案的必要前提 治疗。人类TLE以内侧颞叶的主要病理为特征 脑叶，特别是海马结构和海马旁结构。 已描述了一种内侧颞叶癫痫综合征，这种综合征通常 以神经系统侮辱为典型，然后是无癫痫发作的间歇 慢性癫痫的最终发作。人们普遍认为，一个 癫痫样活动的倾向增加源于不平衡 神经元兴奋和抑制之间的关系，特别是通过 抑制性神经递质γ-氨基丁酸(GABA)。一个 尚未回答的根本问题是这一进程的性质 发生在癫痫持续状态后、无癫痫发作间期 可能会减少GABA能抑制，并导致增加 癫痫样活动。这项建议考察了损伤的演变。 在发病前一段时间内对GABAA受体介导的抑制 使用慢性癫痫的动物模型研究自发性癫痫发作。三 假设：1.GABAA受体介导的变化 海马区CA1区抑制呈递增状态 癫痫并先于慢性癫痫的出现。2.更改 在GABAA受体的药理学中进化并在 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 自发性癫痫的发作。从这些研究中获得的信息 将更好地定义癫痫发作前GABA能缺陷的发展 并将有助于开发新的抗癫痫疗法。

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.