Neuronal Loss and Plasticity in Epilepsy

描述（由申请人提供）： 严重的脑损伤如癫痫持续状态或创伤性脑损伤有可能在以后的生活中产生癫痫。然而，潜伏期往往发生在初始损伤和自发性癫痫发作或癫痫的出现之间。当前的研究旨在确定颞叶癫痫小鼠模型中癫痫持续状态和创伤性脑损伤后发生的进行性形态和生化变化。重点将放在氯离子转运蛋白的潜在变化，在调节神经元兴奋性发挥重要作用。在每个模型的研究中将使用免疫组织化学方法和光学和共聚焦显微镜，以确定顺序变化。第一组研究将确定海马体和其他大脑区域中两种主要氯离子转运蛋白的正常定位，这些区域通常与颞叶癫痫有关。第二组研究将检验以下假设：在癫痫小鼠模型中，氯化物转运蛋白的表达在几个时间点发生改变。这些研究将包括癫痫持续状态后短时间内、自发性癫痫发作前潜伏期、慢性期和自发性癫痫发作后即刻的分析。广泛的假设是氯转运蛋白将以可能降低匹鲁卡品处理动物中GABA能抑制作用的方式改变，从而促进癫痫的发生和自发性癫痫发作的开始。第三组研究将检验以下假设：阻断负责将氯化物移动到神经元中的氯化物转运蛋白将减少齿状回中脆弱神经元的脑损伤。最后一组研究将检验以下假设：GABA系统或氯离子转运蛋白的遗传改变可增加轻度至中度创伤性脑损伤后海马损伤。这些研究的广泛目标是确定癫痫持续状态或头部创伤后可能促进癫痫发展的渐进性变化，从而为设计预防此类变化的治疗方法提供基础。

DESCRIPTION (provided by applicant): Abstract A severe brain insult such as status epilepticus or traumatic brain injury has the potential for producing epilepsy later in life. However, a latent period often occurs between the initial insult and the appearance of spontaneous seizures or epilepsy. The current studies are designed to identify the progressive morphological and biochemical changes that occur following status epilepticus in a mouse model of temporal lobe epilepsy and following traumatic brain injury. Emphasis will be placed on potential changes in chloride transporters that play a major role in regulating neuronal excitability. Immunohistochemical methods with light and confocal microscopy will be used in studies of each model to determine the sequential changes. The first group of studies will identify the normal localization of the two major chloride transporters in the hippocampus and other brain regions that are often involved in temporal lobe epilepsy. A second group of studies will test the hypothesis that expression of the chloride transporters is altered in a mouse model of epilepsy at several time points. These studies will include analyses at short intervals after status epilepticus; during the latent period before spontaneous seizures develop; during the chronic period; and immediately after a spontaneous seizure. The broad hypothesis is that the chloride transporters will be altered in ways that could reduce the effectivenss of GABAergic inhibition in the pilocarpine-treated animals and thus contribute to the development of epilepsy and the initiation of spontaneous seizures. The third group of studies will test the hypothesis that blocking the chloride transporter responsible for moving chloride into neurons will reduce seizure-induced damage of vulnerable neurons in the dentate gyrus. The final group of studies will test the hypothesis that genetic alterations of the GABA system or a chloride transporter can increase hippocampal damage following a mild to moderate traumatic brain injury. The broad goals of the studies are to identify progressive changes that could promote the development of epilepsy following status epilepticus or head trauma and thus provide a basis for designing treatments to prevent such changes.