Mechanisms of Epileptogenesis

癫痫发生机制

• 批准号: 7100198
• 负责人: EDWARD H BERTRAM
• 金额: $ 35.37万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7100198
• 关键词: amygdala; biological signal transduction; electroencephalography; entorhinal cortex; epilepsy; gamma aminobutyrate; hippocampus; immunocytochemistry; laboratory rat; limbic system; neurotransmitter agonist; pathologic process; synapses; thalamus; tissue /cell culture; voltage /patch clamp

DESCRIPTION (provided by applicant): Epilepsy is a chronic condition of spontaneous recurrent seizures that affects about 1% of our population. Although treatment is successful for most patients, one third remain uncontrolled on any of the available medications. Mesial temporal lobe or limbic epilepsy is one of the most common forms of therapy resistant epilepsy. Understanding the basis for this disorder is necessary for the development of more effective therapies. Anatomically this syndrome involves the primary limbic structures such as the hippocampus, amygdala and entorhinal cortex. There is growing evidence for the involvement of subcortical structures in this syndrome as well, and one site of interest is the midline nuclei of the thalamus, including the medial dorsal nucleus and the rhomboid/reuniens complex, which have strong connections to and from the limbic structures. This region shows clear anatomic changes in human imaging studies and in pathology studies in animal models. In the current funding period we have found that the midline thalamus is consistently involved in limbic seizures from the onset, suggesting that this area is part of the primary seizure circuit. In addition we have good evidence that the midline is capable of modulating seizure severity and duration. In this proposal we wish to build on these past findings and examine the means by which this region modulates seizure activity with a focus on the role of GABA, the inhibitory neurotransmitter. In this project we will use two models of limbic seizures and epilepsy to examine three specific questions: 1) Can GABA and its many agonists modulate seizure activity when administered to specific sites in the thalamus? 2) Can the synaptic input from the limbic sites to the midline thalamus, one arm of the hypothesized thalamolimbic seizure loop, be influenced by GABA and its agonists? 3) Are there specific alterations in the pharmacology and physiology of GABA in limbic epilepsy that affect the efficacy of GABA? By focusing on the role of GABA and its modulators in the midline thalamic region, we hope to determine first whether this subcortical area with broad reciprocal limbic connections is a potential target for seizure suppressing therapy, and whether GABA enhancing agents directed to this region can be useful therapeutic agents.

描述（由申请人提供）：癫痫是一种自发性反复发作的慢性疾病，影响约 1% 的人口。尽管大多数患者的治疗是成功的，但三分之一的患者在使用任何可用药物后仍无法控制。内侧颞叶或边缘癫痫是最常见的难治性癫痫形式之一。了解这种疾病的基础对于开发更有效的疗法是必要的。从解剖学上讲，这种综合征涉及主要边缘结构，如海马体、杏仁核和内嗅皮质。越来越多的证据表明皮质下结构也参与了这种综合征，其中一个感兴趣的部位是丘脑的中线核团，包括内侧背核和菱形/reuniens复合体，它们与边缘系统有很强的联系结构。该区域在人类成像研究和动物模型病理学研究中显示出明显的解剖学变化。在当前的资助期间，我们发现中线丘脑从一开始就一直参与边缘癫痫发作，表明该区域是主要癫痫发作回路的一部分。此外，我们有充分的证据表明中线能够调节癫痫发作的严重程度和持续时间。在本提案中，我们希望以这些过去的发现为基础，研究该区域调节癫痫活动的方式，重点关注抑制性神经递质 GABA 的作用。在这个项目中，我们将使用边缘癫痫发作和癫痫的两种模型来研究三个具体问题：1) GABA 及其许多激动剂在丘脑特定部位给药时能否调节癫痫发作活动？ 2）从边缘部位到中线丘脑（假设的丘脑边缘癫痫发作环路的一个臂）的突触输入是否会受到 GABA 及其激动剂的影响？ 3) GABA治疗边缘性癫痫的药理学和生理学是否存在影响GABA疗效的特定改变？通过关注 GABA 及其调节剂在丘脑中线区域的作用，我们希望首先确定这个具有广泛相互边缘连接的皮质下区域是否是癫痫抑制治疗的潜在目标，以及针对该区域的 GABA 增强剂是否可以用于治疗癫痫发作。有用的治疗剂。