Enhanced excitation and epilepsy with chloride channel dysfunction

点击翻译按钮获取中文摘要

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.