0069 Sleep in Drosophila is Regulated by the Chromatin Remodeling Factor ISWI

Abstract

Introduction Sleep is commonly disrupted in patients with neurodevelopmental disorders (NDDs). Despite strong clinical associations between disrupted sleep and other NDD symptoms, we lack an understanding of how these are pathophysiologically related. Drosophila melanogaster exhibit essential characteristics of human sleep and have well-defined neural circuits underlying learning and social behaviors. This represents an ideal system to investigate the mechanistic interaction between disrupted sleep and other behavioral dysfunctions in NDDs. Methods We performed a reverse genetic RNAi-based screen targeting Drosophila homologs of human genes within NDD-associated risk loci. Pan-neuronal knockdown of risk genes was achieved using the Gal4-UAS system. Results Pan-neuronal knockdown of ISWI led to dramatic deficits in sleep and circadian arrhythmicity in the adult fly. Across species, ISWI and its homologs are ATP-dependent chromatin remodelers that regulate gene expression important for neural differentiation. We found that depleting ISWI also leads to memory and social deficits. ISWI functions during dissociable temporal windows of pre-adult development and in different circuits to establish different adult behaviors. The sleep phenotype associated with ISWI knockdown mapped to a specific population of cells. RNA-Seq of developing brains during the window important for sleep deficits revealed significant transcriptional changes in genes associated with nervous system development, suggesting ISWI acts in the development of sleep regulatory circuits. Finally, mutations in the human homologs of ISWI, SMARCA1/5, have been implicated in NDDs. Expressing either SMARCA1/5 in the setting of ISWI knockdown differentially rescued adult deficits. Conclusion Identification of ISWI provides a platform for unraveling pleiotropic behavioral effects from an NDD risk gene. Sleep, circadian rhythms, memory, and social behaviors are affected by ISWI knockdown, and map to different developmental periods and circuits. In addition, SMARCA1/5 differentially rescue adult behaviors, suggesting NDD-causing mutations in these genes may affect different behaviors. Current work aims to determine how human mutations in SMARCA1/5 affect behaviors. Support This work was supported by NIH K08 NS090461 (MSK) and T32 HL007953 (NNG), Hearst Foundation Fellowship 2018 (NNG), Burroughs Welcome Career Award for Medical Scientists, March of Dimes Basil O’Connor Scholar Award, and Sloan Research Fellowship (MSK).