Mechanisms of Epileptogenesis

描述（由申请人提供）：癫痫是一种自发性复发性癫痫发作的慢性疾病，影响约1%的人口。虽然大多数患者的治疗是成功的，但三分之一的患者仍然无法控制任何可用的药物。内侧颞叶或边缘癫痫是最常见的难治性癫痫之一。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系统结构，如海马体、杏仁核和内嗅皮层。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，包括内侧背核和菱形/连合复合体，它们与边缘系统结构有很强的联系。该区域在人类成像研究和动物模型的病理学研究中显示出清晰的解剖学变化。在目前的资助期间，我们发现中线丘脑从一开始就一直参与边缘系统癫痫发作，这表明该区域是主要癫痫发作回路的一部分。此外，我们有很好的证据表明，中线能够调节癫痫发作的严重程度和持续时间。在这个提议中，我们希望建立在这些过去的研究结果，并检查该区域调节癫痫发作活动的方式，重点是GABA，抑制性神经递质的作用。在这个项目中，我们将使用两个模型的边缘癫痫发作和癫痫检查三个具体的问题：1）GABA和它的许多激动剂调节癫痫发作活动时，在丘脑的特定网站？2)从边缘系统到中线丘脑（假设的丘脑边缘系统癫痫发作环路的一个分支）的突触输入能受到GABA及其激动剂的影响吗？3)GABA在边缘系统癫痫中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及其调节剂在中线丘脑区域的作用，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靶点，以及针对该区域的GABA增强剂是否可以是有用的治疗剂。

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.