Enhanced excitation and epilepsy with chloride channel dysfunction

神经网络的兴奋性是由兴奋和抑制之间的平衡来定义的。当这种平衡被打破而有利于兴奋时，网络就会变得过度兴奋。这一观察结果构成了确定癫痫相关病理的一般指导原则。考虑到这一点，人们一直在努力理解定义兴奋性和抑制性神经传递的分子特性。脑抑制的主要来源是神经递质-氨基丁酸（GABA）与GABAA受体亚型的结合，其功能是配体门控氯通道。反过来，这种gabaergy抑制作用取决于神经元膜上氯离子的浓度梯度。CLC2氯离子通道亚型是形成这种梯度的几个通道之一。最近，人们发现几种人类特发性广泛性癫痫（IGEs）与CLC2突变有关。丘脑是一种皮层下结构，是与IGEs相关的癫痫发作活动产生的关键组成部分。然而，CLC2在丘脑中的功能尚不清楚。我提出的项目的目标是了解CLC2中断如何促进丘脑的网络高兴奋性。我的初步结果表明，CLC2功能障碍增强了体外丘脑网络活动的兴奋性。这种网络增强与丘脑神经元亚型的突触兴奋选择性增加是平行的。令人惊讶的是，在CLC2中断期间观察到兴奋性传递的改变，这种效应可能使丘脑网络过度兴奋。我设计了几个实验来确定介导这种增强的突触兴奋的机制。这些实验中有几个依赖于技术——脑电图记录/解释、局部脑灌注、成像技术——我将从同意培训我的顾问那里学习。

Neural network excitability is defined by the balance between excitation and inhibition. When this balance is disrupted in favor of excitation, networks become hyperexcitable. This observation constitutes a general guiding principle for determining the pathologies associated with epilepsy. With this in mind, significant effort has been directed towards understanding the molecular properties that define excitatory and inhibitory neurotransmission. A major source of inhibition in the brain results from the binding of the neurotransmitterY-aminobutyric acid (GABA) to GABAA receptor subtypes, which function as ligand-gated chloride channels. This GABAergic inhibition, in turn, depends on the chloride concentration gradient present across neuronal membranes. The CLC2 chloride channel subtype is one of several channels responsible for establishing this gradient. Recently, it was discovered that several human idiopathic generalized epilepsies (IGEs) are associated with CLC2 mutations. The thalamus, a subcortical structure, is a critical component for the generation of seizure activity associated with the IGEs. However, the function of CLC2 in the thalamus is unknown. The goal of my proposed project is to understand how CLC2 disruptions promote network hyperexcitability in the thalamus. My preliminary results indicate that CLC2 dysfunction enhances the excitability of thalamic network activity in vitro. This network enhancement is paralleled by a selective increase in synaptic excitation onto a subtype of thalamic neurons. While surprising to observe altered excitatory transmission during CLC2 disruption, this effect likely renders thalamic networks hyperexcitable. I have designed several experiments to determine the mechanism mediating this enhanced synaptic excitation. Several of these experiments rely on techniques - EEG recording/interpretation, local brain perfusion, imaging techniques - that I will learn from consultants that have agreed to train me.