Mechanisms of benign neonatal familial convulsions

仔细研究罕见的孟德尔式人类神经系统疾病的基因是一个强大的 了解常见相关疾病的病因、治疗和潜在治愈方法。的 神经元KCNQ基因是最近发现的，作为寻找导致良性肿瘤的突变基因的结果。 家族性新生儿惊厥，一种常染色体显性遗传的癫痫综合征， 婴儿期和整个生命。神经元KCNQ基因突变也会导致肌震颤（周围神经 疾病）和耳聋。KCNQ基因编码电压依赖性钾通道的亚单位。 长期目标是了解这些神经元KCNQ的体内功能 通道，以便更好地了解基本的大脑信号机制，并利用这些机制， 神经治疗学 KCNQ通道通过其内在的电压门控活性调节神经元的兴奋性， 在大脑中的特定位置，并通过它们作为神经递质受体的效应器的能力， 细胞内信号通路。确定KCNQ通道在大脑中的具体位置 电路，以及受体，通路和相互作用的蛋白质如何调节它们在大脑中的活动， 增强我们利用这些通道作为治疗靶点的能力， 兴奋性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通道上，而以前的 调查人员和其他人的工作表明，KCNQ渠道发挥着重要作用。它开拓了新的 具有KCNQ 2突变和癫痫发作易感性增加的表型的可用突变小鼠， 自发性癫痫 具体目的是：（1）定位KCNQ亚基在哺乳动物中的分布 正常和突变啮齿动物发育和成熟大脑中的隔海马网络;（2）定义 靶向KCNQ亚基至轴突起始节段和Ranvier节的机制;以及（3）分析KCNQ亚基在轴突起始节段和Ranvier节中的表达。 轴突KCNQ通道在亚细胞和细胞水平的功能。

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.