Excitatory GABA, Interneuron Networks, and Epilepsy

兴奋性 GABA、中间神经元网络和癫痫

• 批准号: 7033927
• 负责人: KATHERINE L PERKINS
• 金额: $ 24.18万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033927
• 关键词: GABA receptor; action potentials; aminopyridines; cellular polarity; electrophysiology; gamma aminobutyrate; gap junctions; genetically modified animals; green fluorescent proteins; guinea pigs; hippocampus; interneurons; laboratory mouse; neuropathology; neurophysiology; neurotransmitter transport; partial seizure; pyramidal cells; synapses; temporal lobe /cortex disorder; voltage /patch clamp

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.

描述（由申请人提供）：顽固性颞叶癫痫患者的脑组织表现出自发性癫痫样活动，该活动依赖于 GABA 介导的传播。这一发现强调了在 GABA 能传递完整的简单模型中研究癫痫突触机制的必要性。主要研究者一直在研究豚鼠海马中的 4-氨基吡啶癫痫模型，这是在存在完整 GABA 能传递的情况下发生的癫痫的良好模型。在该模型中，巨大的 GABA 突触后电位 (GPSP) 是由中间神经元网络介导的同步 GABA 释放到锥体细胞上引起的，直接发生在每个癫痫样事件之前。基本假设是 GPSP 的去极化成分正在触发癫痫样事件。另外还假设锥体细胞中的癫痫样放电被促进，因为“反馈”中间神经元在 GPSP 产生后难以控制。这项研究的长期目标是确定海马中神经元间突触连接的功能性质以及中间神经元网络在该大脑区域的突触生理学和病理生理学中的作用。该项目解决了三个重要问题：1) 中间神经元到中间神经元的突触机制，使海马中的 GABA 同步释放；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 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的，以及 促惊厥。电生理学以及药理学工具将用于解决这些问题。来自视觉定位的中间神经元的细胞附着和全细胞记录将构成该研究的关键部分。拟议的研究具有创新性，因为它研究了 GABA 能神经元的同步活动如何促进癫痫样活动。了解在完整的 GABA 能传输存在下发生的癫痫样活动的机制可能会导致开发出对现有药物具有耐药性的癫痫新药物疗法；特别是，这些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。