Mechanisms of Epileptogenesis

描述（由申请人提供）：癫痫是一种自发复发性癫痫发作的慢性疾病，约占我国人口的1%。尽管治疗对大多数病人来说是成功的，但仍有三分之一的病人无法控制任何可用的药物。内侧颞叶或边缘癫痫是治疗性癫痫最常见的形式之一。了解这种疾病的基础对于开发更有效的治疗方法是必要的。从解剖学上讲，这种综合征涉及初级边缘结构，如海马体、杏仁核和内嗅皮层。越来越多的证据表明，这种综合征也涉及皮质下结构，其中一个令人感兴趣的部位是丘脑的中线核，包括内侧背核和菱形/重连复合体，它们与边缘结构有很强的联系。该区域在人体成像研究和动物模型病理研究中显示出明显的解剖变化。在目前的资助期内，我们发现丘脑中线从发病开始就一直与边缘癫痫发作有关，这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。在这个建议中，我们希望建立在这些过去的发现和检查的手段，通过该区域调节癫痫活动，重点是GABA的作用，抑制性神经递质。在这个项目中，我们将使用两种边缘癫痫发作和癫痫模型来研究三个具体问题：1)GABA及其许多激动剂在给予丘脑特定部位时能否调节癫痫发作活动？2)从边缘部位到丘脑中线的突触输入是否会受到GABA及其激动剂的影响？3)边缘癫痫中GABA的药理学和生理学是否存在特异性改变，影响GABA的疗效？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的互易边缘连接的皮层下区域是否是癫痫抑制治疗的潜在靶点，以及针对该区域的GABA增强剂是否可以成为有用的治疗剂。

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.