A Complex Containing the Na+/K+ ATPase Regulates Epileptogenesis in Drosophila melanogaster

Abstract

Epileptogenesis, the process through which the brain becomes seizure-prone, is not well understood. Previous work identified a novel gene in Drosophila, julius seizure (jus), that when mutated or developmentally knocked down, leads to epilepsy in adult Drosophila, providing a useful model for dissecting epileptogenesis. Here we report that when a GFP-tagged Jus was used as bait in a co-immunoprecipitation (co-IP) assay, a complex of 23 associated proteins was identified that included ATPalpha and Nervana 3, two subunits of the Na+/K+ ATPase. RNAi-mediated knockdown of ATPalpha, Nervana 3, or any of 8 additional complex proteins enhanced seizure susceptibility of jus mutants. The critical period for Jus expression to protect against epileptogenesis was further defined, occurring between pupal stages P4-7; remarkably, the jus seizure phenotype could be rescued by increasing neural activity of jus-expressing neurons during these mid-pupal stages, suggesting that altered neural activity in these neurons may contribute to the seizure phenotype. Our data support a model that, in wild type flies, a protein complex containing Na+/K+ ATPase and Jus prevents epileptogenesis, possibly by regulating neural activity.