Mechanisms of benign neonatal familial convulsions

描述（由申请人提供）：仔细研究罕见孟德尔形式的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、治疗和潜在治愈的有力方法。神经元KCNQ基因是最近发现的，作为寻找导致良性家族性新生儿惊厥的突变基因的结果，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期的癫痫发作相关。神经元KCNQ基因突变也会导致肌震颤（一种周围神经疾病）和耳聋。KCNQ基因编码电压依赖性钾通道的亚基。拟议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大脑信号传导机制，并利用这些机制进行神经治疗。KCNQ通道通过其在脑中特定位置的内在电压门控活性以及通过其作为神经递质受体和细胞内信号传导途径的效应器的能力来调节神经元兴奋性。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质如何调节其在脑中的活性，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或调节性神经传递的改变和失衡，如癫痫和疼痛综合征。目前的建议集中在海马体轴突上的KCNQ通道，研究人员和其他人以前的工作表明KCNQ通道起着重要作用。它利用了新获得的突变小鼠与KCNQ 2突变和表型增加癫痫发作的易感性和自发性癫痫发作。具体目标是：（1）定位KCNQ亚基在正常和突变啮齿动物发育和成熟脑中隔海马网络中的定位;（2）确定KCNQ亚基靶向轴突起始段和Ranvier节点的机制;（3）在亚细胞和细胞水平上分析轴突KCNQ通道的功能。

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.