The role of sodium channels in shaping neuronal circuit output

描述（由申请人提供）：电压门控钠（Nav）通道对神经系统功能至关重要。事实上，各种各样的通道病已被归因于许多人类Nav通道的突变，这些通道是几种抗癫痫药物的靶点。遗传上易处理的模式生物果蝇是一个有吸引力的系统，以探讨Nav通道功能的作用，修改模式的活动的神经回路。一个单一的基因，麻痹（帕拉），编码所有已知的Nav通道亚型，和一个集合的分子特征的突变等位基因已被链接到不同的神经元兴奋性的改变。有趣的是，观察到的帕拉突变表型平行的频谱人类钠通道病。此外，Nav通道表达的减少抑制了其他突变体类别中的过度活跃表型，例如Kv通道突变体（例如Shaker）中麻醉诱导的摇动和bang敏感突变体（例如容易休克）中机械休克诱导的癫痫发作。我建议研究如何定义的改变在个别等位基因的导航通道功能的中央模式发生器的尖峰活动的形状，以及如何这样的修改导航通道相互作用与超兴奋KV和爆炸敏感的突变体。 本申请的具体目的是：1）使用广泛研究的高度定型的中枢模式发生器，证明果蝇中的帕拉（Nav通道基因）在产生结构化尖峰活动中的控制。遗传学、电生理学和计算方法的组合将能够以精确的定量术语分析刻板输出如何被不同的Nav通道突变修饰。2)确定不同的对位突变如何改变电路功能，通过与超兴奋突变的相互作用揭示，包括在KV和bang敏感突变体中发现的那些。产生双突变体的帕拉与突变基因座引起振动或爆炸敏感的表型将提供重要的线索方面的Nav通道的抑制或增强这种超兴奋性的作用。 总之，这些目标将显示修改后的Nav通道活动如何在更广泛的兴奋性环境中相互作用，形成各种异常的尖峰模式，这是一个与理解几种神经系统疾病的病因相关的基本问题。作为一个培训计划，该项目促进跨学科的方法来解决神经科学中的基本问题，申请人Atulya Iyengar将能够整合必要的遗传，生理和定量知识和技能，成长为一个独立的生物医学研究人员，在神经遗传学方面做出原创性贡献。

DESCRIPTION (provided by applicant): Voltage gated sodium (Nav) channels are critical to nervous system function. Indeed, a diverse array of channelopathies has been attributed to mutations in a number of human Nav channels, which are the targets of several anti-epileptic drugs. The genetically tractable model organism Drosophila melanogaster is an attractive system to explore the role of Nav channel function on modifying patterned activities of neural circuits. A single gene, paralytic (para), encodes all known Nav channels isoforms, and a collection of molecularly characterized mutant alleles has been linked to distinct alterations in neuronal excitability. Interestingly, the observed para mutant phenotypes parallel the spectrum of human sodium channelopathies. Furthermore, reduction of Nav channel expression suppresses the hyperactive phenotypes in other mutant categories, such as anesthesia- induced shaking in Kv channel mutants (e.g. Shaker) and mechanical shock-induced seizures in bang-sensitive mutants (e.g. easily shocked). I propose to study how defined alterations of Nav channel function in individual alleles shape the spiking activity of a central pattern generator, and how such modifications to Nav channels interact with hyperexcitable Kv and bang-sensitive mutants. The specific aims of this application are to: 1) Demonstrate the control by para, the Nav channel gene in Drosophila, in the generation of structured spiking activity, using an extensively studied, highly stereotypic central pattern generator. A combination of genetic, electrophysiological and computational approaches will enable the analysis of how stereotypic output is modified by distinct Nav channel mutations in precise quantitative terms. 2) Determine how different mutations of para alter circuit function as revealed by interaction with hyperexcitable mutations, including those found in Kv and bang-sensitive mutants. Generating double mutants of para with mutant loci causing either shaking or bang-sensitive phenotypes will provide important clues into the aspects of Nav channels that act on the suppression or enhancement of such hyperexcitability. Taken together, the aims will show how modified Nav channel activity interacts in the broader excitability environment in shaping spike patterns of a wide spectrum of abnormalities, a fundamental question with relevance to understanding the etiology of several neurological disorders. As a training plan, this project fosters an interdisciplinary approach to address basic questions in neuroscience, and the applicant, Atulya Iyengar, will be able to integrate the necessary genetic, physiological, and quantitative knowledge and skills to grow into an independent biomedical researcher making original contributions in neurogenetics.