Enhanced excitation and epilepsy with chloride channel dysfunction

癫痫是美国第二常见的神经疾病-- 第一种是偏头痛--估计要花费20亿美元 每年一次。特发性全身性癫痫(IGES)是最常见的 这种疾病的遗传形式。而IGES的病因是 人们对此知之甚少，有证据表明，丘脑的病理环路 皮质下的大脑结构，是原因。有几个因素决定了 丘脑内神经回路的兴奋性。一个关键组件是 网状丘脑(RT)核内神经元的数量。RT神经元是 GABA能，正常情况下对丘脑有很强的抑制作用。这 抑制将丘脑产生癫痫的可能性降至最低 活动。Clc2氯通道在丘脑中高度表达， 对于建立RT神经元的兴奋性很重要。事实上，有证据表明 提示编码CLC2的基因突变会导致丘脑回路 变得过度兴奋，可能是某些IGES的基础。我的数据显示 CLC2功能障碍增强RT神经元的兴奋，从而潜在地 使他们能够克服RT神经元抑制的抗癫痫作用。 我的项目旨在确定导致反应时过度兴奋的机制(S) CLC2中断期间的神经元。我为此设计了几个实验 结束。因为这些实验中的一些使用了我已经限制的技术 专业知识-脑电记录/解释、局部脑灌注、成像 技巧--我已经组建了一个团队，顾问们已经同意培训我。1 在我的K99/R00的K99阶段接受了这样的培训。我现在申请 对于我的K99/R00的独立阶段。我将作为一名 弗吉尼亚大学药理学系助理教授。 这所大学为我提供了足够的空间/资源来开展 我在提案中概述的实验。我从2011年8月24日开始。

Epilepsy is the second most common neurological disorder in the United States - the first being migraine headaches - and is estimated to cost the US $2 billion annually. The idiopathic generalized epilepsies (IGEs) are the most common of the genetically acquired forms of the disease. While the etiology of the IGEs is poorly understood, evidence suggests that pathological circuits in the thalamus, a subcortical brain structure, are the cause. Several factors establish the excitability of neural circuits within the thalamus. One critical component is a population of neurons within the reticular thalamic (RT) nucleus. RT neurons are GABAergic and normally exert a powerful inhibitory effect on the thalamus. This inhibition minimizes the likelihood that the thalamus will generate epileptic activity. The CLC2 chloride channel is highly expressed in the thalamus and is important for establishing the excitability of RT neurons. Indeed, evidence suggests that mutations in the gene encoding CLC2 cause thalamic circuits to become hyperexcitable and may underlie some IGEs. My data indicates that CLC2 dysfunction strengthens the excitation of RT neurons, thereby potentially enabling them to overcome the anti-epileptic effects of RT neuron inhibition. My project aims to determine the mechanism(s) that causes over-excitation of RT neurons during CLC2 disruption. I have designed several experiments to this end. As some of these experiments utilize techniques with which I have limited expertise - EEG recording/interpretation, local brain perfusion, imaging techniques - I have assemble a team consultants that have agreed to train me. 1 have received such training during the K99 phase of my K99/R00. I now apply for the independent phase of my K99/R00. I will carry out this phase as an assistant professor in the pharmacology department at the University of Virginia. The university has provided me with sufficient space/resources to carry out the experiments I have outlined in my proposal. I begin August 24, 2011.