Enhanced excitation and epilepsy with chloride channel dysfunction

癫痫是美国第二常见的神经系统疾病- 第一种是偏头痛，估计花费20亿美元 每年。特发性全身性癫痫（IGE）是最常见的 这种疾病的遗传形式。虽然政府间专家组的病因是 尽管我们对此知之甚少，但有证据表明，丘脑中的病理回路， 大脑皮层下结构是原因有几个因素确立了 丘脑内神经回路的兴奋性一个关键的组成部分是 网状丘脑（RT）核内的神经元群体。RT神经元是 正常情况下对丘脑产生强大的抑制作用。这 抑制使丘脑产生癫痫的可能性最小化， 活动CLC 2氯离子通道在丘脑中高度表达， 这对建立RT神经元的兴奋性很重要。事实上， 表明编码CLC 2的基因突变导致丘脑回路 变得过度兴奋，并可能成为某些IGE的基础。我的数据显示 CLC 2功能障碍加强RT神经元的兴奋，从而可能 使它们能够克服RT神经元抑制的抗癫痫作用。 我的项目旨在确定导致RT过度兴奋的机制 CLC 2破坏期间的神经元。我为此设计了几个实验 端由于这些实验中的一些使用的技术， 专业知识- EEG记录/解释、局部脑灌注、成像 技术-我已经召集了一个团队的顾问，他们同意培训我。1 在我的K99/R 00的K99阶段接受过此类培训。我现在申请 我的K99/R 00的独立阶段我将把这一阶段作为 弗吉尼亚大学药理学系的助理教授。 大学为我提供了足够的空间/资源来开展 我在我的建议中提到的实验。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.