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：
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
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/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

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. 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）通道对于神经系统功能至关重要。实际上，各种各样的通道病归因于许多人类NAV通道中的突变，这些通道是几种抗癫痫药的靶标。遗传上可牵引的模型有机体果蝇是一个有吸引力的系统，可探索NAV通道功能在修改神经回路的图案活动中的作用。单个基因瘫痪（Para）编码所有已知的NAV通道同工型，并且分子表征的突变等位基因的集合已与神经元兴奋性的不同变化有关。有趣的是，观察到的para突变表型与人类通道病的光谱平行。此外，NAV通道表达的降低可抑制其他突变类别中的多活活表型，例如在KV通道突变体（例如振动器）中麻醉诱导的摇动和机械冲击诱导的爆炸敏感突变体的癫痫发作（例如，易于冲击）。我建议研究单个等位基因中NAV通道函数的定义变化如何塑造中央模式发生器的尖峰活动，以及对NAV通道的这种修饰如何与过度可见的KV和爆炸敏感突变体相互作用。该应用程序的具体目的是：1）使用广泛研究的，高度刻板的中央模式发生器来证明果蝇中的NAV通道基因Para（果蝇中的NAV通道基因的控制）。遗传，电生理学和计算方法的结合将能够分析如何通过精确的定量术语来通过不同的NAV通道突变来改变刻板印象。 2）确定与与过度抗性突变相互作用（包括在KV和爆炸敏感突变体中发现的）相互作用所揭示的不同的Para改变电路功能的不同突变。用突变体基因座产生双重突变体，导致摇动或对爆炸敏感的表型，将为抑制或增强这种过度刺激性的NAV通道的各个方面提供重要的线索。综上所述，目的将表明修改后的NAV通道活动如何在更广泛的兴奋性环境中相互作用，以塑造广泛异常的尖峰模式，这是一个基本问题，与理解几种神经系统疾病的病因相关。作为一个培训计划，该项目促进了一种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，以成长为独立的生物医学研究人员，使原始的生物医学研究人员成为原始的原始研究人员神经遗传学的贡献。公共卫生相关性：电压门控钠通道对于单个神经元和整个神经系统的适当功能至关重要。该项目的目的是阐明改变钠通道功能的机制会破坏神经元电路的模式活性。遗传，电生理和计算技术将用于评估电路功能，并以定量术语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疾病的病因（例如癫痫）具有直接的影响。