Epileptogenesis: Causes, Consequences and Treatment

描述(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。这是一种症状状态，即与先前的侮辱有关的情况。脑损伤后致痫的病理改变的发生过程在很大程度上是未知的。这项建议的目的是阐明致痫对大脑的侮辱所引发的机制，这些侮辱结合在一起使最初的损伤难以治疗，并继续引发一连串的事件，最终导致癫痫。一旦确定了致痫过程中的关键事件，将启动更多的研究来干预这些病理过程的发展，并评估这是否会降低癫痫的严重程度或阻止随后的发展。这个项目结合了三名主要研究人员的专业知识，以及神经生理学、生物化学和分子生物学的专业知识。这种方法的组合允许调查人员之间的协同互动，并构成了该计划的重要优势。本提案将结合电生理、分子、生化和整个动物的方法，阐明1)损伤引发的抑制性突触内代谢过程的变化如何影响抑制效果并使海马体易于在TLE中癫痫发作；2)GABA受体转运如何通过脑损伤而改变，进而导致癫痫，这些转运改变如何有助于癫痫持续状态的进行性难治性；以及3)确定旨在阻断致痫损伤后动物明显的代谢和受体转运改变的干预措施是否可能是阻止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痫改变的性质是促进开发新的治疗策略以更好地治疗甚至治愈这种进行性和破坏性疾病的绝对先决条件。

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.