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。 公共卫生相关性： 与退伍军人健康的相关性癫痫持续状态以及其他急性脑损伤，如头部创伤，是影响许多退伍军人的严重健康问题。虽然原因可能不同，但每种情况下的一个问题是从最初的脑损伤恢复后可能发生癫痫。需要进行基础研究，以确定受伤后大脑发生的渐进性变化，以便制定预防性治疗。这些研究将集中在GABA系统的变化，这是大脑中的一个主要神经递质系统，以及控制细胞内Cl-水平的氯（Cl-）转运蛋白，从而帮助确定GABA系统在控制癫痫发作活动方面的有效性。拟议研究的目的是确定潜在的因素，可能有助于神经元的损失和癫痫发作的发展后，癫痫持续状态和创伤性脑损伤。识别这些因素可能会导致新的治疗策略的发展。

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. PUBLIC HEALTH RELEVANCE: Relevance to Veterans Health Status epilepticus as well as other acute brain insults, such as head trauma, are serious health problems that affect many Veterans. Although the causes may vary, a concern in each case is the possible development of epilepsy following recovery from the initial brain insult. Basic research is needed to identify progressive changes in the brain that occur following the injury in order to develop preventive treatment. The studies will focus on changes in the GABA system, a major neurotransmitter system in the brain, and chloride (Cl-) transporters that control the level of intracellular Cl- and thus help determine how effective the GABA system will be in controlling seizure activity. The goal of the proposed studies is to identify underlying factors which could contribute to loss of neurons and seizure development following status epilepticus and traumatic brain injury. Identifying such factors could lead to the development of new treatment strategies.