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的亚基。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、通路和相互作用蛋白如何调节它们在大脑中的活动，将增强我们利用这些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，如癫痫和疼痛综合征。目前的建议主要关注海马轴突上的KCNQ通道，研究者和其他人的先前工作表明KCNQ通道在其中发挥重要作用。它利用了KCNQ2突变和表型增加的癫痫易感性和自发癫痫的新突变小鼠。具体目的是：(1)绘制正常和突变鼠类发育和成熟大脑中KCNQ亚基在哺乳动物中隔海马网络中的定位图；(2)明确了KCNQ亚基定位于Ranvier轴突初始段和节点的机制；(3)分析轴突KCNQ通道在亚细胞和细胞水平上的功能。

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, pathways and interacting proteins modulate their activity in the brain, will enhance our ability to exploit these channels as therapeutic targets in conditions involving excessive excitability or alterations and imbalances in modulatory neurotransmission, such as epilepsy and pain syndromes. The current proposal focuses on KCNQ channels on axons in hippocampus, where previous work by the investigator and others indicates KCNQ channels play important roles. It exploits newly available mutant mice with KCNQ2 mutations and phenotypes of increased seizure susceptibility and spontaneous seizures. The specific aims are to: (1) map the localization of KCNQ subunits in mammalian septohippocampal networks in developing and mature brain of normal and mutant rodents; (2) define the mechanisms targeting KCNQ subunits to axon initial segments and nodes of Ranvier; and (3) analyze the function of axonal KCNQ channels at the subcellular and cellular level.