The role of sodium channels in shaping neuronal circuit output

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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.