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

基本信息

批准号：
8729900
负责人：
Atulya Srisudarshan Ram Iyengar
金额：
$ 2.31万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
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/8729900
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 biophysical properties central pattern generator density interdisciplinary approach mutant nervous system disorder neural circuit neurogenetics neuronal excitability skills voltage

项目摘要

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.

描述（由申请人提供）：电压门控钠（Nav）通道对于神经系统功能至关重要。事实上，多种通道病可归因于许多人类 Nav 通道的突变，而这些通道是多种抗癫痫药物的靶点。遗传上易于处理的模式生物果蝇是一个有吸引力的系统，可用于探索 Nav 通道功能在改变神经回路模式活动中的作用。单个基因 paralytic (para) 编码所有已知的 Nav 通道亚型，并且一系列分子特征突变等位基因与神经元兴奋性的不同改变有关。有趣的是，观察到的对位突变表型与人类钠离子通道病谱相似。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）中麻醉引起的摇晃和爆炸敏感突变体（例如容易电击）中机械冲击引起的癫痫发作。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心模式发生器的尖峰活动，以及对 Nav 通道的这种修改如何与超兴奋的 Kv 和爆炸敏感突变体相互作用。该应用的具体目标是： 1) 使用广泛研究的、高度刻板的中心模式发生器，展示果蝇中 Nav 通道基因 para 在结构化尖峰活性生成中的控制。遗传、电生理学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 通道突变如何修改刻板输出。 2) 确定副回路的不同突变如何通过与超兴奋突变（包括 Kv 和 bang 敏感突变体中发现的突变）相互作用来揭示功能。产生具有引起震动或爆炸敏感表型的突变位点的para双突变体将为了解Nav通道抑制或增强这种过度兴奋性的方面提供重要线索。总而言之，这些目标将展示修改后的 Nav 通道活动如何在更广泛的兴奋性环境中相互作用，形成多种异常的尖峰模式，这是与了解几种神经系统疾病的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员，做出原创性的研究。在神经遗传学方面的贡献。