GABAergic regulation of entorhino-hippocampal excitability in epilepsy.

描述（由申请人提供）：颞叶癫痫（TLE）是成人中最常见的癫痫形式，并且经常对药物治疗产生抗药性，呈现出巨大的社会和医疗问题。然而，颞叶癫痫的细胞和突触机制尚不清楚。来自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，我们发现一种主要的体周突出的篮状细胞选择性地支配在海马外的MEC第二层的主细胞，但避免邻近的细胞产生通往齿状回的穿孔通路。在这里，我们提出验证这样的假设，即在TLE中，对内鼻皮层输出的高度专一的局部gabaergy控制被显著破坏，gabaergy抑制受损构成了内鼻-海马网络中高兴奋性和自发性癫痫的关键机制。该假设将在慢性癫痫期TLE的重复低剂量盐酸盐模型中进行验证，并通过配对记录电生理和免疫细胞化学方法进行评估，辅以数据驱动的大规模计算建模方法。本提议的实验是专门针对细胞突触机制下的TLE。我们预计，明确实验性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。

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.