The chromatin remodeler ISWI acts during <i>Drosophila</i> development to regulate adult sleep

Abstract

Sleep disruptions are among the most commonly reported symptoms across neurodevelopmental disorders (NDDs), but mechanisms linking brain development to normal sleep are largely unknown. From a <i>Drosophila</i> screen of human NDD-associated risk genes, we identified the chromatin remodeler <i>Imitation SWItch/SNF</i> (<i>ISWI</i>) to be required for adult fly sleep. Loss of <i>ISWI</i> also results in disrupted circadian rhythms, memory, and social behavior, but <i>ISWI</i> acts in different cells and during distinct developmental times to affect each of these adult behaviors. Specifically, <i>ISWI</i> expression in type I neuroblasts is required for both adult sleep and formation of a learning-associated brain region. Expression in flies of the human <i>ISWI</i> homologs <i>SMARCA1</i> and <i>SMARCA5</i> differentially rescues adult phenotypes, while de novo <i>SMARCA5</i> patient variants fail to rescue sleep. We propose that sleep deficits are a primary phenotype of early developmental origin in NDDs and point toward chromatin remodeling machinery as critical for sleep circuit formation.