CELLULAR AND IONIC MECHANISMS OF EPILEPTOGENESIS

本项目的长期目标是研究慢性肾功能衰竭的发病机制。 癫痫的发生。拟议的工作涉及在以下方面运行的基本流程 慢性癫痫脑，特别是在海马区(HC)和 毗邻的海马旁结构是颞叶的重要区域 肺叶癫痫(TLE)。研究的重点是癫痫患者的HC-PHC环路 引发和放大癫痫发作的网络。中国的三个关键地区 将研究HC-PHC环路，每个环路都有自己的致痫特征-- 海马齿状回(DG)、内嗅皮层(EC)和大脑皮质CA1区。 HC-PHC环在癫痫发作发生和加重中的作用 此外，S的慢性改变增加了癫痫的发生 针对已建立的TLE慢性模型定义了三个研究区域 并在我们的实验室中进行了表征。在过去的支持期间， 已经达到了几个研究目标，包括：开发体外 包含所有选定的HC-PHC研究区域的切片制备； 用尖尖电极实现细胞内记录； CA1区GABA能中间神经元“休眠”的论证 研究正常和正常细胞外和细胞内方面的能力 DG和EC的致痫反应；带来斑片记录和 将电压钳位技术应用于实验室；并在 最不确定的慢性TLE类型，在我们的动物模型中和在 人类，表现出选择性的第三层EC神经元的丢失 对欧洲委员会所到的偏远地点的癫痫发作加剧负责 项目，也许，在欧共体。我们的研究将扩展这项工作，并 检验制衡通常相反的中心假设 HC-PHC环的高致痫电位在 慢性癫痫患者大脑功能连接性的改变。一个 体外和体内实验的结合将测试4个推论 这一假设：抑制性中间神经元的推论1-休眠是一种 整个HC-PHC环路的一般属性；推论2-慢性 抑制性中间神经元的癫痫休眠对 局部回路对过度兴奋驱动的反应紊乱，但 由于自发活动，对休息条件的重要性较低 GABA能中间神经元；推测兴奋性突触存在于 HC-PHC环中的慢性癫痫；推论4--除了局部 回路改变(推论1-3)，远端部位改变发生在慢性 HC-PHC环路有癫痫。这些研究将提供洞察力， 协助更好地治疗癫痫患者。

The long range goal of this project is to study mechanisms of chronic epileptogenesis. The work proposed relates to basic processes operating in chronically epileptic brains, particularly within the hippocampus (HC) and adjacent parahippocampal (pHC) structures as important regions for temporal lobe epilepsy (TLE). Studies are focused on the HC-pHC loop, an epileptic network that initiates and amplifies seizures. Three key regions in the HC-pHC loop, each with its own epileptogenic features, will be examined-- the dentate gyrus (Dg), entorhinal cortex (EC), and CA1 area of the HC. The operation of the HC -pHC loop in generating and intensifying seizures as well s chronic alterations imparting increased epileptogenesis to the three study regions have been defined for chronic models of TLE developed and characterized in our laboratory. In the past period of support, several research aims have been met, including: development of an in vitro slice preparation containing all the chosen study areas of the HC-pHC; implementation of intracellular recordings with sharp electrodes; demonstration of "dormancy" of GABAergic interneurons in CA1; establishing the ability to study extra- and intracellular aspects of normal and epileptogenic responses in the DG and EC; bringing patch recording and voltage-clamping techniques to athe laboratory; and establishing that at least certain "types" of chronic TLE, both in our animal models and in humans, display a selective loss of layer III EC neurons that seems responsible for heightened epileptogenesis at remote sites to which the EC projects and, perhaps, in the EC. Our studies will extend this work and test the central hypothesis that checks and balances which normally oppose the high epileptogenic potential of the HC-pHC loop are disturbed in the chronically epileptic brain by changes in functional connectivity. A combination of in vitro and in vivo experiments will test 4 corollaries of this hypothesis: Corollary 1-dormancy of inhibitory interneurons is a general property throughout the HC-pHC loop; Corollary 2-in chronic epilepsy dormancy of inhibitory interneurons is of greater importance for disturbed reactivity of local circuites to excessive excitatory drive but of less importance for resting conditions because of spontaneous activity of GABAergic interneurons; Corollary 3-altered excitatory synapses exist in chronic epilepsy in the HC-pHC loop; Corollary 4-in addition to local circuit changes (Corollaries 1-3), remote site changes occur in chronic epilepsy in the HC-pHC loop. These studies will provide insight that will assist in better treating epileptic patients.