Defining Behavioral Gene Networks for Austism Spectrum Disorder Genes Using Sleep and Circadian Rhythms

Sleep and circadian (~24 h) rhythm disturbances are prevalent in as many as 80% of those suffering from autism spectrum disorders (ASD). Indeed, sleep disruption may be an important contributor to the core neurodevelopmental, cognitive, and social deficits emblematic of ASD. Understanding the mechanistic basis of sleep disruption in ASD promises to reveal novel therapeutic avenues. Over 150 genetic loci have been identified as likely contributing to the risk of ASD. Yet for most of these genes it is unclear how they function in vivo to contribute to ASD related symptoms. We and others have shown that genetic manipulation of some ASD gene orthologs in fly and mouse models results in ASD related impairments, including disrupted circadian rhythms and sleep. In fact, fly models have even led to the development of novel therapeutics. ASD results, in part, from the inheritance of multiple genetic factors and synergistic allele-specific interactions among them may play an important role in disease manifestation. Yet how the plethora of ASD risk genes interact with each other within gene networks remains a major challenge to understanding how genetic risk contributes to disease. Here we will employ novel high throughput behavioral genetic models of ASD risk genes in Drosophila that recapitulate features of ASD sleep and circadian disruption. As a tool to discover ASD gene networks important for sleep and circadian rhythms, we propose to use in vivo behavioral screening of transgenic RNA interference llbraries in both wild-type flies and flies sensitized with disruptions of ASD risk genes. Remarkably, the genetic bases of circadian rhythms and sleep are conserved between flies and humans, the discovery of which led to the awarding of the 2017 Nobel Prize. Moreover, human ASD risk genes have clear Drosophila orthologs that function in molecular and cellular pathways, e.g., synapses, that are also highly conserved between flies and humans. Flies are inexpensive to handle, a