Grant Abstract: Ameliorating Hyperexcitability in the Nervous System Through Dietary Omega-3 Fatty Acids

Grant Number: 1R01NS146457-01A1
PI Name: Iyengar
Project Title: Ameliorating Hyperexcitability in the Nervous System Through Dietary Omega-3 Fatty Acids

Abstract: Diet is an important factor affecting normal brain function and the manifestation of neurological disorders. Indeed, there is intense interest in discovering specific dietary changes that reduce disease burden, as these interventions are often readily accessible to patients. Identifying and optimizing such approaches requires a basic understanding of the precise molecular, developmental and physiological underpinnings of diet- dependent plasticity in the structure and/or function of the nervous system. Studies of diet-dependent plasticity phenomena in genetically tractable model organisms can leverage systematic and precise molecular and cellular manipulations to uncover the salient biological processes involved. This project builds upon a serendipitous finding that trace quantities of dietary milk whey lipids improve neurological phenotypes in Drosophila carrying the Shudderer mutation (Shu), a gain-of-function allele of the voltage-gated sodium channel gene para. In Shu mutants, dietary milk whey attenuates both hyperexcitable behaviors (e.g. convulsions, and ataxia) and electrophysiological activity (e.g. spontaneous spike discharges and ectopic motor neuron firing). Whey also improves phenotypes in many hyperexcitable fly mutants and remarkably reduces epilepsy-related phenotypes in a mouse model of Dravet syndrome. Recently, we found ω-3 polyunsaturated fatty acids (PUFAs) are the key component for neuromodulation, with transient supplementation (<24 h) in the larval stage improving adult phenotypes. Central premise: ω-3 PUFAs act during pupation (metamorphosis) to stabilize excitability across the nervous system. During pupation, most neurons comprising the adult brain develop, while the few persisting larval neurons retract and retarget their processes. Hypothesis: in Shu pupae, ω-3 PUFAs suppress hyperexcitability by altering the developmental profile of key neurons and/or glia sub-populations. Aim #1 Resolve molecular signaling mechanisms underlying ω-3 PUFA-mediated hyperexcitability suppression. Preliminary findings indicate TRP channels mediate changes induced by dietary ω-3 PUFAs. Using a combination of genetic, behavioral, electrophysiological and metabolomic approaches, the signaling pathway (receptors, ligands and cell types) underlying ω-3 PUFA-dependent hyperexcitability suppression will be delineated. Aim #2 Establish alterations in the nervous system’s developmental trajectory following ω-3 PUFA supplementation. Intact pupal imaging approaches enable whole-brain structural and Ca2+ imaging. In Shu mutants, critical neurodevelopmental differences and the progression of hyperexcitability phenotypes will be established. Parallel experiments will determine how dietary ω-3 PUFAs modulate these features. Project outcomes will rigorously delineate basic biological processes mediating dietary ω-3 PUFAs’ effect on nervous system structure and function. The parallel observations in fly and mouse epilepsy models, indicates project findings will have a clear long-term translational potential in the context of neuronal excitability disorders.

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