Compromised GABA Recycling as an Epileptogenic Mechanism

颞叶癫痫（Temporal lobe epilepsy，TLE）是成人最常见的癫痫综合征，也是最常见的癫痫综合征。 难对付这是一种症状性疾病，即与先前的侮辱有关。所涉及的过程 脑损伤后病理性致癫痫改变的产生在很大程度上是未知的。我们提供 GABA再循环机制在动物大脑抑制性突触中受损的证据 关于TLE GABA的再循环是释放后重新装载突触囊泡所必需的， 确定抑制性突触动态调节活动区域中回路兴奋性的能力， 个脑袋本建议中的研究旨在专门测试我们的中心假设： GABA再循环机制的损害是癫痫发生的关键早期事件。此外，委员会认为， 在致痫性损伤后早期恢复正常的GABA产生将是一种可行的治疗方法 干预，能够减缓癫痫的严重程度或治愈癫痫的后续发展。研究 针对测试我们的中心假设将集中在4个具体目标：目标1：确定 海马抑制性突触中介导GABA产生和再循环的主要机制 慢性癫痫动物目的2：确定GABA再循环发生改变的时间过程 癫痫发生的机制目的3：确定替代GABA的功能后果 再循环机制在调节癫痫动物海马的兴奋性，并评估 恢复谷氨酸-谷氨酸循环功能的机制。目标4：确定恢复策略 谷氨酰胺-谷氨酸循环功能，或增强GABA能突触产生GABA的能力， 在发展癫痫的过程中的动物的替代机制。结合使用 电生理学，分子和整个动物的方法，目前的建议将阐明如何 抑制性突触内代谢过程的变化损害了抑制功效， 海马体与癫痫发作的关系此外，我们将确定如何早期干预， 这些病理生理过程可以改变疾病的进展。了解癫痫的本质 功能、分子和整个动物水平的变化是促进 开发新的治疗策略，以更好地治疗甚至治愈这种毁灭性的疾病。

Temporal lobe epilepsy (TLE) is the most common epileptic syndrome in adults, and also the most intractable. It is a symptomatic condition, i.e. one associated with a prior insult. The processes involved in generation of pathological, epileptiogenic alterations following brain injury are largely unknown. We provide evidence that GABA recycling mechanisms are compromised in inhibitory synapses in the brains of animals with TLE. GABA recycling is required to reload synaptic vesicles following release, a critical function determining the ability of inhibitory synapses to dynamically regulate circuit excitability in active areas of brain. Studies in the present proposal are designed to specifically test our CENTRAL HYPOTHESIS: Compromise in GABA recycling mechanisms is a pivotal, early event in epileptogenesis. Furthermore, restoration of normal GABA production early following an epileptogenic injury will be a viable therapeutic intervention, capable of blunting the severity of or curing the subsequent development of epilepsy. Research directed at testing our central hypothesis will focus on 4 SPECIFIC AIMS: AIM 1: Determine the predominant mechanisms mediating GABA production and recycling in hippocampal inhibitory synapses of chronically epileptic animals. AIM 2: Determine the time course of onset of altered GABA recycling mechanisms during epileptogenesis. AIM 3: Determine the functional consequences of alternate GABA recycling mechanisms in regulating excitability of the hippocampus in epileptic animals, and assess mechanisms to restore glutamine-glutamate cycle function. AIM 4: Determine strategies to either restore glutamine-glutamate cycle function, or enhance the capacity of GABAergic synapses to produce GABA by alternate mechanisms in animals which are in the process of developing epilepsy. Using a combination of electrophysiological, molecular, and whole animal approaches, the present proposal will elucidate how changes in metabolic processes within inhibitory synapses compromise inhibitory efficacy and predispose the hippocampus to seizure generation in TLE. Furthermore, we will determine how early interventions in these pathophysiologic processes may alter disease progression. Understanding the nature of epileptogenic changes at the functional, molecular, and whole animal level is an absolute prerequisite to facilitate the development of new therapeutic strategies to better treat and perhaps cure this devastating disorder.