GABAergic regulation of entorhino-hippocampal excitability in epilepsy.

描述(申请人提供)：颞叶癫痫(TLE)是成人中最常见的癫痫形式，经常对药物治疗产生抗药性，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却知之甚少。人类和动物模型的大量证据表明，内侧内嗅皮层(MEC)在TLE的发生和维持中起关键作用。最近，我们发现一类主要的周向同构投射篮子细胞选择性地支配MEC第二层的主细胞，这些主细胞投射到海马体外，而不是邻近的细胞，这些细胞产生了通往齿状回的穿支通路。在这里，我们建议检验一种假设，即在TLE中存在正常高度专门化的局部GABA能控制TLE内嗅皮层输出的显著干扰，并且受损的GABA能抑制构成了内嗅-海马网络中高兴奋性和自发性癫痫发作的关键机制。这一假说将在慢性癫痫阶段TLE的重复低剂量海人酸模型中得到验证，评估将通过成对记录的电生理和免疫细胞化学方法进行，并辅之以数据驱动的大规模计算建模方法。这项提议的实验是专门针对TLE背后的细胞-突触机制设计的。预计确定实验性TLE对MEC神经元的功能后果将有助于未来新的抗癫痫治疗策略的发展。 公共卫生相关性：许多颞叶癫痫患者有反复的自发性癫痫发作，而现有的药物治疗无法控制这些发作。自发癫痫可能是由持续受损的抑制回路引起的，这些抑制回路是在突然受到侮辱后出现的。该项目将确定内脑皮层-海马区回路的异常抑制调节是否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.