Physiology of Status Epilepticus In Vitro

体外癫痫持续状态的生理学

• 批准号: 7473840
• 负责人: DOUGLAS A COULTER
• 金额: $ 40.04万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7473840
• 关键词: AMPA Receptors; Adult; Animals; Birth; Birth Rate; Characteristics; Chronic; Condition; DNA Sequence Rearrangement; Development; Disease; Epilepsy; Equilibrium; Frequencies; Gatekeeping; Generations; Glutamate Receptor; Hippocampus (Brain); In Vitro; Intervention; Mediating; Molecular; Nature; Neurons; Newborn Infant; Numbers; Parents; Physiology; Pilocarpine; Predisposition; Process; Property; Recurrence; Research; Research Design; Research Personnel; Role playing therapy; Seizures; Severities; Status Epilepticus; Structure; Syndrome; Temporal Lobe Epilepsy; Testing; Tissues; Transgenic Organisms; Zinc; dentate gyrus; gamma-Aminobutyric Acid; granule cell; in vivo; mossy fiber; neural circuit; novel therapeutics; receptor expression

DESCRIPTION (provided by applicant): Temporal lobe epilepsy is the most common epileptic syndrome in adults, and also the most intractable. It is considered to be a symptomatic condition, i.e. one associated with a prior insult. For the most part, the mechanisms mediating the pathological alterations causing epilepsy remain to be elucidated. The present proposal wilt explore synaptic circuit, cellular and molecular alterations in the hippocampal dentate gyrus, and assess the effects of these alterations on seizure frequency and severity in intact, epileptic animals. Studies are designed to specifically test our CENTRAL HYPOTHESIS: Cellular and circuit alterations evident in the epileptic dentate gyrus combine to generate a tonic imbalance in function, which compromises the normal 'gatekeeper' function of this region, and results in a hippocampus which is predisposed to generate seizures. To test this hypothesis, the cellular and circuit properties of the dentate gyrus are to be studied in tissue isolated from epileptic animals, and pharmacological and transgenic interventions are to be explored in intact animals, examining effects on seizure frequency and severity. Research directed at testing our central hypothesis will focus on 3 SPECIFIC AIMS: AIM 1: Determine the role played by zinc released from sprouted mossy fiber terminals in dentate gyrus circuit hyperexcitability in epileptic animals. AIM 2: Determine the role played by birth of large numbers of new dentate granule cells triggered by the development of epilepsy in the subsequent emergence of dentate gyrus circuit hyperexcitability characteristic of chronic temporal lobe epilepsy AIM 3. Determine the effects of zinc released from sprouted mossy fiber recurrent collaterals and of the birth of large numbers of new neurons on seizure frequency and severity in epileptic animals. Using a combination of electrophysiological, molecular, and whole animal approaches, the present proposal will attempt to better understand how divergent cellular and circuit alterations may interact to predispose the hippocampus to seizure generation in temporal lobe epilepsy. Understanding the nature of epileptogenic changes at the functional, molecular, and whole animal level is necessary to achieve to facilitate the development of new therapeutic strategies to better treat and perhaps cure this devastating disorder.

描述（由申请人提供）：颞叶癫痫是成年人中最常见的癫痫综合症，也是最棘手的癫痫综合症。它被认为是一种有症状的疾病，即与先前的侮辱相关的情况。在大多数情况下，介导导致癫痫病的病理改变的机制仍有待阐明。本提案WILT探索了海马齿状回的突触回路，细胞和分子改变，并评估这些改变对完整，癫痫动物的癫痫发作频率和严重程度的影响。研究旨在特异性检验我们的中心假设：癫痫齿状回和电路的变化结合在功能上产生滋补不平衡，这会损害该区域的正常“守门员”功能，并导致海马室，可产生持久性癫痫发作。为了检验该假设，应在从癫痫动物分离的组织中研究齿状回的细胞和电路性能，并在完整的动物中探索药理学和转基因干预措施，以检查对癫痫发作频率和严重程度的影响。针对测试我们的中心假设的研究将重点关注3个特定目的：目标1：确定从发芽的苔藓纤维末端释放的锌末端的作用。目的2：确定通过癫痫发育的发展触发的大量新齿状颗粒细胞在随后出现的齿状回电路的出现而引起的，这是慢性颞叶癫痫的过度特征的特征。使用电生理学，分子和整个动物方法的结合，本提案将尝试更好地理解不同的细胞和电路变化如何相互作用，以使海马在颞叶癫痫病中癫痫发作产生癫痫发作。必须了解在功能，分子和整个动物水平上的癫痫发生变化的性质，对于促进新的治疗策略的发展是必要的，以更好地治疗或治愈这种毁灭性的疾病。