PHYSIOLOGY OF STATUS EPILEPTICUS IN VITRO

癫痫持续状态的体外生理学

• 批准号: 6187791
• 负责人: DOUGLAS A COULTER
• 金额: $ 28.4万
• 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 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6187791
• 关键词: NMDA receptors; anticonvulsants; benzodiazepines; central neural pathway /tract; confocal scanning microscopy; entorhinal cortex; excitatory aminoacid; generalized seizures; hippocampus; laboratory rat; neural conduction; neural inhibition; neural plasticity; neural transmission; neuropharmacology; neurophysiology; synapses; voltage /patch clamp

DESCRIPTION: Temporal lobe epilepsy (TLE) is a symptomatic condition, associated with known precipitating causes. Implicit in this statement is the concept that, following an insult, TLE develops in an otherwise normal brain. The mechanisms involved in generation of pathological central nervous system alterations underlying the development of epilepsy remain to be elucidated. The present proposal will explore cellular and molecular alterations occurring in the hippocampus in two animal models of TLE. In both of these models, following an initial severe seizure, animals recover, and then begin to develop spontaneous limbic seizures within 2-3 weeks. Using these spontaneously epileptic animals, the applicant intends to investigate physiological and molecular alterations in the function of synaptic transmission in the hippocampus. The central hypothesis of this proposal is that the hyperexcitability in the limbic system in animals with TLE is due at least in part to pathological loss of inhibitory function, which triggers regionally selective alterations in the balance of hippocampal excitatory and inhibitory synaptic transmission. In order to test this hypothesis, GABAergic inhibitory synaptic transmission will be studied in both control and epileptic animals, to explore potential epilepsy-associated alterations in this system in the hippocampus. Alterations in GABAergic inhibitory function are to be studied at two main time points. One focus of research will be to examine alterations in the epileptic hippocampus at a chronic, end stage point, where the seizure disorder is fully developed. A second focus of research will be to examine the development of alterations in GABAergic receptor function during the latent period, prior to expression of seizures. Changes in inhibitory synaptic transmission, postsynaptic GABA-A receptor physiology and pharmacology, and relative levels of expression of GABA-A receptor subunit mRNAs are to be assessed using patch clamp recording techniques in brain slices and acutely isolated cells, as well as molecular techniques to examine expression of GABA receptor subunit mRNAs in individual cells. It is hoped that through these combined techniques, epileptogenic alterations in GABAergic neurotransmission can not only be identified, but the molecular mechanisms involved in generating these permanent changes in the properties of the epileptic brain can begin to be identified. Understanding of the nature of epileptogenic changes at both the functional and molecular levels is necessary to achieve in order to some day have the potential to develop a cure for this devastating disorder.

描述：颞叶癫痫（TLE）是一种症状状况， 与已知的沉淀原因有关。 在此语句中隐含的是 侮辱后，TLE以原本正常的形式发展的概念 脑。 病理中心产生的机制 癫痫发展的基础神经系统改变仍在 阐明。 目前的建议将探索细胞和分子 在两个TLE动物模型中，海马中发生的改变。 在 这两种模型，在初始严重癫痫发作后，动物恢复， 然后开始在2-3周内开始自发癫痫发作。 使用这些自发癫痫动物，申请人打算 研究生理和分子变化的功能 海马中的突触传播。 中心假设 提议是，动物的边缘系统中的过度兴奋性 TLE至少部分归因于抑制功能的病理丧失， 这会触发区域选择性改变 海马兴奋性和抑制性突触传播。 为了 检验此假设，GABA能抑制性突触传播将是 在对照和癫痫动物中进行了研究，以探索潜力 海马中该系统中癫痫相关的变化。 在两个主要 时间点。 研究的重点是检查 癫痫发作的癫痫发作，癫痫发作 疾病已完全发育。 研究的第二个重点是检查 GABA能受体功能变化期间的发展 潜在时期，在表达癫痫发作之前。 抑制性的变化 突触传播，突触后GABA-A受体生理和 GABA-A受体亚基的药理学和相对水平 将使用斑块夹记录技术评估mRNA 切片和急性分离的细胞，以及分子技术 检查单个细胞中GABA受体亚基mRNA的表达。 它 希望通过这些组合技术，癫痫发生变化 在GABA能神经传递中，不仅可以鉴定出来，还可以鉴定出分子 产生这些属性的这些永久变化的机制 可以开始识别癫痫大脑的大脑。 理解 在功能和分子水平上癫痫发生变化的性质 为了某一天而有必要实现，有可能发展 治愈这种毁灭性疾病。