Sleep disorders are common in patients diagnosed with autism spectrum disorders (ASD), being present in upward of 80% of ASD youths. The sleep disruptions frequently last into adulthood, but it has been difficult to elucidate a common neurobiological cause of these sleep disruptions. Previous research into this phenomenon has noted circadian rhythm defects, frequent nighttime waking, and an overall reduction in nighttime sleep: symptoms similar to what is reported in animal knock-out models of NRNX1, a synaptic plasticity gene implicated in ASD. NRXN1 is currently known to interact with post- synaptic proteins to stabilize synapses and promote neurite outgrowth, potentially acting as a common source for both sleep disruptions and for neurite overgrowth phenotypes observed in ASD. Therefore, identifying morphological changes in wake-promoting neurons during a cycling 24-hour time period will be a necessary precursor to identifying a common molecular pathway for both ASD and sleep disorders. In Drosophila, PDF neurons are an important part of the wake-promoting circuit, and are necessary for the generation of stable sleep patterns. Recently, it has been shown that PDF neurons undergo extensive remodeling, demonstrating cyclical periods of pruning and regrowth, over a 24 hour time period. While previous studies have demonstrated the presence of Nrx-1, the Drosophila homologue for NRXN1, in wake-promoting PDF neurons, it remains to be seen if the loss of Nrx-1 significantly impacts the remodeling cycle observed in healthy animals. As part of the proposed research, I will develop a Drosophila model of ASD by expressing human NRXN1 in a Nrx-1 null background. Specifically, I will evaluate if the loss of Nrx-1 significantly alters the cyclical remodeling of Drosophila PDF neurons, and whether this effect can be rescued by the expression of human reference NRXN1 or ASD-associated variant. I will then determine if this effect is sufficient to disrupt sleep bouts, variations in the circadian rhythm, or alterations in stereotyped social behavior. This proposed work will yield a new model with which to evaluate the effects of genes that contribute to synaptic plasticity and provide needed information about the neurobiology of both sleep and ASD.
This proposal aims to improve our understanding of the common neurobiological and genetic mechanisms which contribute to both sleep disruptions and autism spectrum disorders. Additionally, the methods proposed here will serve as a framework for the further interrogation of synaptic proteins and the role they play in neurological disorders, including autism spectrum disorders and schizophrenia.
