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，各种各样的通道病变被归因于许多人类Nav通道的突变，这些通道是几种抗癫痫药物的靶点。遗传易学的模式生物黑腹果蝇是探索Nav通道功能在神经回路模式活动中的作用的一个有吸引力的系统。一个单一基因，麻痹（para），编码所有已知的Nav通道同种异构体，并且一组分子特征突变等位基因与神经元兴奋性的明显改变有关。有趣的是，观察到的对突变型表型与人类钠通道病的谱相似。此外，Nav通道表达的减少抑制了其他突变类型的过度活跃表型，例如Kv通道突变体（例如Shaker）的麻醉诱导的震动和bang敏感突变体（例如容易震动）的机械冲击诱导的癫痫发作。我建议研究单个等位基因中Nav通道功能的明确改变如何塑造中央模式发生器的尖峰活动，以及这种对Nav通道的修改如何与超兴奋Kv和bangsensitive突变体相互作用。本应用程序的具体目的是：1)利用广泛研究的、高度定型的中枢模式发生器，证明果蝇Nav通道基因para在产生结构化尖峰活动中的控制作用。遗传、电生理和计算方法的结合将能够以精确的定量方式分析不同的Nav通道突变如何改变定型输出。2)通过与超兴奋突变（包括Kv和bang-sensitive突变）的相互作用，确定para - alter circuit的不同突变是如何发挥作用的。产生具有突变位点的para双突变体，导致震动或砰砰敏感表型，将为研究Nav通道抑制或增强这种高兴奋性提供重要线索。综上所述，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，形成广泛的异常谱的尖峰模式，这是一个与理解几种神经系统疾病病因相关的基本问题。作为一项培训计划，该项目培养了一种跨学科的方法来解决神经科学的基本问题，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，成长为一名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.