Mechanisms of benign neonatal familial convulsions

描述（由申请人提供）：仔细研究罕见的孟德尔型人类神经系统疾病的基因是深入了解常见相关疾病的原因、治疗和潜在治愈方法的有力途径。神经元KCNQ基因是最近在寻找引起良性家族性新生儿惊厥的突变基因时发现的，良性家族性新生儿惊厥是一种常染色体显性癫痫综合征，与婴儿期和整个生命中的癫痫发作有关。神经元KCNQ基因的突变也会导致肌萎缩症（一种周围神经紊乱）和耳聋。KCNQ基因编码电压依赖性钾通道亚基，这项工作的长期目标是了解这些神经元KCNQ通道的体内功能，以便更好地了解基本的脑信号机制，并利用这些机制进行神经治疗。KCNQ通道通过其内在的，在大脑特定位置的电压门控活动调节神经元的兴奋性，并通过它们作为神经递质受体和细胞内信号通路的效应器的能力。确定KCNQ通道在脑回路中的具体位置，以及受体和通路如何调节它们在大脑中的活动，将增强我们利用m通道作为治疗靶点的能力，这些靶点涉及过度兴奋性或调节性神经传递的改变和不平衡，如癫痫、疼痛综合征和阿尔茨海默病。目前的研究主要集中在间隔区和海马体中的特定脑回路，以及特定的突触前和突触后定位，研究者和其他人之前的工作表明KCNQ通道在其中起着重要作用。具体目的是：(1)绘制哺乳动物发育和成熟大脑中隔海马网络中KCNQ亚基的定位图；(2)明确了KCNQ2亚基在脑、脊髓和周围神经的Ranvier轴突初始节段和节点的靶向和稳定机制；(3)分析由于KCNQ2亚基显性阴性突变表达而表现出高兴奋性和癫痫的突变小鼠系中KCNQ通道的定位和功能。

DESCRIPTION (provided by applicant): Careful study of genes responsible for rare mendelian forms of human neurological disorders is a powerful approach for gaining insight into the causes, treatment, and potential cure for common, related diseases. The neuronal KCNQ genes were recently discovered as the result of the search for mutant genes causing Benign Familial Neonatal Convulsions, an autosomal dominant epileptic syndrome associated with seizures in infancy and throughout life. Mutations in neuronal KCNQ genes also result in myokymia (a peripheral nerve disorder) and deafness. The KCNQ genes encode subunits of voltage-dependent potassium channels The long term goals of the proposed work is to understand the in vivo functions of these neuronal KCNQ channels, in order to better understand basic brain signaling mechanisms and to exploit these mechanisms for neurological therapeutics. KCNQ channels regulate neuronal excitability through their intrinsic, voltage-gated activity at particular locations in brain, and through their ability to serve as effectors for neurotransmitter receptors and intracellular signaling pathways. Determining specifically where KCNQ channels are localized in brain circuits, and how receptors and pathways modulate their activity in the brain, will enhance our ability to exploit M-channels as therapeutic targets in conditions involving excessive excitability or alterations and imbalances in modulatory neurotransmission, such as epilepsy, pain syndromes, and Alzheimer's disease. The current proposal focuses on particular brain circuits in the septum and hippocampus, and particular presynaptic and post-synaptic localizations, where previous work by the investigator and others indicates KCNQ channels play important roles. The specific aims are to: (1) map the localization of KCNQ subunits in mammalian septohippocampal networks in developing and mature brain; (2) define the mechanisms of targeting and stabilization of KCNQ2 subunits at axon initial segments and nodes of Ranvier in brain, spinal cord, and peripheral nerve; and (3) analyze the localization and function of KCNQ channels in lines of mutant mice that exhibit hyperexcitability and epilepsy due to expression of a dominant-negative mutant of the KCNQ2 subunit.