The role of sodium channels in shaping neuronal circuit output

钠通道在塑造神经元回路输出中的作用

• 批准号: 8457175
• 负责人: Atulya Srisudarshan Ram Iyengar
• 金额: $ 2.71万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2015-07-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457175
• 关键词: Address; Affect; Alleles; Anesthesia procedures; Anesthetics; Animal Model; Antiepileptic Agents; Attenuated; Biomedical Research; Categories; Collection; Computational Technique; Defect; Disease; Drosophila genus; Drosophila melanogaster; Employee Strikes; Environment; Epilepsy; Etiology; Fostering; Functional disorder; Generations; Genes; Genetic; Goals; Homologous Gene; Human; Individual; Ion Channel; Knowledge; Leg; Lesion; Link; Mechanics; Modification; Molecular; Motor Activity; Mutation; Nervous System Physiology; Nervous system structure; Neurobiology; Neurons; Neurosciences; Output; Paralysed; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Potassium Channel; Property; Protein Isoforms; RNA Splicing; Research Personnel; Role; Seizures; Shapes; Shock; Sodium; Sodium Channel; Structure; System; Training; Vertebrates; Work; central pattern generator; density; interdisciplinary approach; mutant; nervous system disorder; neural circuit; neurogenetics; neuronal excitability; skills; voltage

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. PUBLIC HEALTH RELEVANCE: Voltage-gated sodium channels are critical for the proper function of individual neurons and the nervous system as a whole. The goal of this project is to elucidate the mechanisms by which altering sodium channel function disrupts patterned activity of neuronal circuits. Genetic, electrophysiological and computational techniques will be utilized to assess circuit function and in quantitative terms delineate the modes of dysfunction caused by distinct sodium channel mutations. The findings of this work will have direct implications in understanding the etiology of neuronal excitability disorders, such as epilepsy.

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，一系列不同的通道病变被归因于一些人类NAV通道的突变，这些通道是几种抗癫痫药物的靶标。遗传易感性的模式生物黑腹果蝇是探索NAV通道功能在改变神经回路模式活动中的作用的一个有吸引力的系统。一个单一的基因，paralytic(Para)，编码所有已知的NAV通道亚型，一系列分子特征的突变等位基因与神经元兴奋性的明显变化有关。有趣的是，观察到的副突变表型与人类钠通道病的谱系相似。此外，NAV通道表达的减少抑制了其他突变类别中的过度活跃表型，如麻醉诱导的Kv通道突变体(例如Shaker)的颤动和机械休克诱导的bang敏感突变体的癫痫发作(例如易休克)。我建议研究单个等位基因中NAV通道功能的明确变化如何塑造中央模式生成器的尖峰活动，以及这种对NAV通道的修改如何与超兴奋的Kv和Bang敏感突变体相互作用。这项应用的具体目的是：1)利用一个被广泛研究的、高度定型的中央模式生成器，展示果蝇NAV通道基因parA在产生结构化的尖峰活动中的控制。遗传学、电生理学和计算方法的结合将能够以精确的数量分析不同的NAV通道突变是如何改变刻板印象的输出的。2)通过与超兴奋突变的相互作用，包括在Kv和Bang敏感突变体中发现的突变，确定对Alter回路的不同突变如何发挥作用。产生双突变的parA与突变的基因座引起的震动或冲击波敏感的表型，将提供重要线索的NAV通道方面的作用，以抑制或增强这种超兴奋性。综上所述，这些目标将展示修改的NAV通道活动如何在更广泛的兴奋性环境中相互作用，以形成广泛异常的棘波模式，这是一个与理解几种神经疾病的病因相关的基本问题。作为一项培训计划，该项目促进了解决神经科学基本问题的跨学科方法，申请者Atulya Iyengar将能够整合必要的遗传、生理和数量知识和技能，成长为在神经遗传学方面做出原创性贡献的独立生物医学研究人员。 与公共健康相关：电压门控钠通道对于单个神经元和整个神经系统的正常功能至关重要。这个项目的目标是阐明钠通道功能改变扰乱神经元回路模式活动的机制。将利用遗传学、电生理学和计算技术来评估电路功能，并定量描述由不同的钠通道突变引起的功能障碍模式。这项工作的发现将对理解神经元兴奋性障碍的病因学有直接影响，如癫痫。