GABAergic regulation of entorhino-hippocampal excitability in epilepsy.

描述（由申请人提供）：颞叶癫痫（TLE）是成年人中最常见的癫痫形式，并且经常对药物治疗产生耐药性，呈现出巨大的社会和医学问题。然而，颞叶癫痫的细胞和突触机制知之甚少。人类和动物模型的大量证据表明，内侧内嗅皮层（MEC）在TLE的产生和维持中起着关键作用。最近，我们发现，一类主要的perisomatically投射篮状细胞选择性地支配主细胞在第二层的MEC的海马外的项目，但避免相邻的细胞，引起的穿孔通路的齿状回。在这里，我们建议测试的假设，有一个显着的中断正常高度专业化，局部GABA能控制内嗅皮层输出TLE，和受损的GABA能抑制构成了一个关键的机制，潜在的过度兴奋和自发性癫痫发作的内嗅-海马网络。该假设将在慢性癫痫阶段的TLE的重复低剂量红藻氨酸模型中进行测试，并且将使用成对记录电生理和免疫细胞化学方法进行评估，并辅以数据驱动的大规模计算建模方法。该提议的实验旨在专门针对TLE的细胞突触机制。预计确定实验性TLE对MEC神经元的功能影响将有助于未来开发新的抗癫痫治疗策略。 公共卫生相关性：许多颞叶癫痫患者有反复自发性癫痫发作，不能用现有的药物治疗控制。自发性癫痫发作可能是由沉淀损伤后出现的持续受损的抑制回路引起的。该项目将确定是否异常抑制调节的内鼻-海马电路有助于癫痫发作的产生。

DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and frequently becomes resistant to drug therapy, presenting an enormous social and medical problem. However, the cellular and synaptic mechanisms underlying epilepsy in the temporal lobe are poorly understood. There is substantial evidence from both humans and animal models indicating that the medial entorhinal cortex (MEC) plays critical roles in the generation and maintenance of TLE. Recently, we discovered that a major class of perisomatically projecting basket cells selectively innervate principal cells in layer II of the MEC that project outside the hippocampus, but avoid the neighboring cells that give rise to the perforant pathway to the dentate gyrus. Here we propose to test the hypothesis that there is a significant disruption of the normally highly specialized, local GABAergic control of entorhinal cortical output in TLE, and that the compromised GABAergic inhibition constitutes a key mechanism underlying hyperexcitability and spontaneous seizures in the entorhino- hippocampal network. The hypothesis will be tested in the repeated low dose kainate model of TLE during the chronic epilepsy phase, and the assessment will be carried out with paired recording electrophysiological and immunocytochemical methods, complemented by data-driven, large-scale computational modeling approaches. The experiments of this proposal are designed to specifically target cellular-synaptic mechanisms underlying TLE. It is anticipated that defining the functional consequences of experimental TLE on neurons in the MEC will help the future development of novel anti-epileptic treatment strategies. PUBLIC HEALTH RELEVANCE: Many patients with temporal lobe epilepsy have repeated spontaneous seizures that cannot be controlled with existing drug therapies. Spontaneous seizures may be caused by persistently compromised inhibitory circuits that emerge after precipitating insults. The project will determine whether aberrant inhibitory regulation of the entorhino-hippocampal circuits contributes to the generation of seizures.