Epileptogenesis: Causes, Consequences and Treatment

描述（由申请人提供）：颞叶癫痫（TLE）是成人最常见的癫痫综合征，也是最难治的。这是一种症状性疾病，即与先前的侮辱有关。脑损伤后病理性致癫痫改变的产生过程在很大程度上是未知的。本提案的目的是阐明致痫性脑损伤引发的机制，这些机制联合收割机使初始损伤难以治疗，并继续引发一系列事件，最终导致癫痫。一旦确定了癫痫发生过程中的关键事件，将启动其他研究以干预这些病理过程的发展，并评估这是否降低了癫痫的严重程度或阻断了癫痫的后续发展。该计划结合了三个主要研究人员的专业知识，在神经生理学，生物化学和分子生物学的专业知识。这种方法的组合允许研究人员之间的协同互动，并构成了该计划的显着优势。本研究综合运用电生理学、分子生物学和整体动物研究方法，阐明1）损伤引起的抑制性突触内代谢过程的变化如何影响抑制效应并使海马易于在TLE中发生癫痫发作;以及2）GABA受体运输如何可能被继续诱导癫痫的脑损伤改变，以及这些运输改变如何导致癫痫持续状态的进行性难治性，以及3）确定设计用于阻断致癫痫损伤后动物中明显的代谢和受体运输改变的干预是否可能是阻断癫痫发展的可行策略。在功能，分子和整个动物水平上了解致癫痫变化的性质是促进新治疗策略发展的绝对先决条件，以更好地治疗并治愈这种进行性和破坏性疾病。

DESCRIPTION (provided by applicant): 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, epileptogenic alterations following brain injury are largely unknown. The objectives of this proposal are to elucidate the mechanisms initiated by epileptogenic insults to the brain which combine to make the initial injury difficult to treat, and which go on to initiate a cascade of events culminating in epilepsy. Once pivotal events in the epileptogenic process are identified, additional studies are to be initiated to intervene in the development of these pathological processes, and assess whether this reduces the severity of or blocks the subsequent development of epilepsy. This program combines the expertise of three principal investigators, with expertise in neurophysiology, biochemistry, and molecular biology. This combination of approaches allows for synergistic interactions between investigators, and constitutes a significant strength of the program. Using a combination of electrophysiological, molecular, biochemical and whole animal approaches, the present proposal will elucidate 1) how injury-initiated changes in metabolic processes within inhibitory synapses compromise inhibitory efficacy and predispose the hippocampus to seizure generation in TLE; and 2) how GABA receptor trafficking may be altered by brain injuries which go on to induce epilepsy, and how these trafficking alterations may contribute to progressive intractabilty in status epilepticus, as well as 3) determine whether interventions designed to block metabolic and receptor trafficking alterations evident in animals following epileptogenic injuries may be viable strategies to block epilepsy development. 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 progressive and devastating disorder.