Mechanisms of benign neonatal familial convulsions

仔细研究导致罕见的孟德尔式人类神经疾病的基因是强有力的 了解常见相关疾病的病因、治疗方法和潜在治疗方法的方法。这个 神经性KCNQ基因是最近发现的，这是寻找导致良性疾病的突变基因的结果 家族性新生儿惊厥，一种与癫痫发作相关的常染色体显性遗传性癫痫综合征 婴儿期和终身期。神经性KCNQ基因突变也会导致肌萎缩症(一种外周神经 紊乱)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的体内功能 为了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通道通过其固有的电压门控活动调节神经元的兴奋性。 大脑中的特定位置，并通过它们作为神经递质受体和 细胞内信号通路。明确确定KCNQ通道在大脑中的定位 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 增强我们利用这些渠道作为治疗靶点的能力，在涉及过度 兴奋性或调节性神经传递的改变和失衡，如癫痫和疼痛 综合症。目前的建议集中在海马区轴突上的KCNQ通道，以前的 研究人员和其他人的工作表明，KCNQ渠道发挥着重要作用。它开发了新的 具有KCNQ2突变和癫痫易感性增加表型的可用突变小鼠 自发性癫痫。 具体目的是：(1)定位哺乳动物的KCNQ亚基 正常和突变啮齿动物发育和成熟脑中的隔海马网；(2)确定 将KCNQ亚基靶向Ranvier轴突起始节段和节点的机制；以及(3)分析 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.