Excitatory GABA, Interneuron Networks, and Epilepsy

描述(申请人提供)：顽固性颞叶癫痫患者的脑组织表现出自发的癫痫样活动，这依赖于GABA介导的传递。这一发现强调了在GABA能传递完整的简单模型中研究癫痫的突触机制的必要性。这位首席研究员一直在研究豚鼠海马区的4-氨基吡啶癫痫模型，这是一个在GABA能传递完整的情况下发生癫痫的很好的模型。在该模型中，由神经元间网络介导的同步GABA释放到锥体细胞所引起的巨大GABA能突触后电位(GPSP)直接先于每个癫痫样事件。潜在的假设是，GPSP的去极化成分触发了癫痫样事件。另外还假设，锥体细胞的癫痫样放电是因为“反馈”中间神经元在GPSP的产生后是难于实现的。本研究的长期目标是确定海马区神经元间至神经元间突触连接的功能性质，以及神经元间网络在该脑区突触生理学和病理生理学中的作用。本项目解决了三个要点：1)神经元间到神经元间的突触机制，使海马区能够同步释放GABA；2)GABA能神经元中的这种同步活动如何促进癫痫样活动；3)去极化的GABA和GABAB成分如何相互作用，以确定突触释放的GABA是抑制性的，还是兴奋性和促惊厥性的。电生理学以及药理学工具将被用来解决这些问题。细胞附着和视觉定位中间神经元的全细胞记录将构成这项研究的关键部分。这项拟议的研究是创新的，因为它检查了GABA能神经元中的同步活动可能有助于癫痫样活动的方式。了解在完整的GABA能传递存在的情况下发生的癫痫样活动的机制可能会导致开发对现有药物耐药的癫痫的新药物疗法；特别是，实验可能证明需要开发针对GABA介导的兴奋性传递的特定药理学工具，或防止GABAB介导的传递减少的药物。

DESCRIPTION (provided by applicant): Brain tissue from patients with intractable temporal lobe epilepsy displays spontaneous epileptiform activity which is dependent upon GABA-mediated transmission. This finding underscores the need for studying synaptic mechanisms of epilepsy in a simple model in which GABAergic transmission is intact. The principal investigator has been studying the 4-aminopyridine model of epilepsy in guinea pig hippocampus, which is a good model for epilepsy occurring in the presence of intact GABAergic transmission. In this model, giant GABAergic postsynaptic potentials (GPSPs), which are caused by interneuron network-mediated synchronous GABA release onto pyramidal cells, directly precede each epileptiform event. The underlying hypothesis is that the depolarizing component of the GPSP is triggering the epileptiform events. It is additionally hypothesized that the epileptiform discharges in pyramidal cells are facilitated because "feedback" interneurons are refractory following the generation of the GPSP. The long-term goal of this study is to identify the functional nature of interneuron-to interneuron synaptic connections in the hippocampus and the role of interneuron networks in the synaptic physiology and pathophysiology of this brain region. This project addresses three important points: 1) Interneuron to interneuron synaptic mechanisms which enable synchronous GABA release in the hippocampus 2) How this synchronous activity in GABAergic neurons facilitates epileptiform activity and 3) How the depolarizing GABA and GABAB components interact to determine whether the synaptically-released GABA is inhibitory or rather is excitatory and proconvulsant. Electrophysiology, along with pharmacological tools, will be used to address these questions. Cell-attached and whole-cell recording from visually-located interneurons will form a key part of the study. The proposed research is innovative because it examines the way in which synchronous activity in GABAergic neurons may work to facilitate epileptiform activity. Understanding the mechanism for epileptiform activity which occurs in the presence of intact GABAergic transmission may lead to the development of new drug therapies for epilepsies which are resistant to currently available drugs; in particular, the experiments may demonstrate the need for development of specific pharmacologic tools targeting excitatory transmission mediated by GABA, or drugs which prevent a reduction in GABAB -mediated transmission.