Diurnal Experimental Models to Investigate Neural Mechanisms of Sleep Disturbance in Smith-Magenis Syndrome

摘要

Abstract Sleep problem is a common but underappreciated comorbidity in many neurodevelopmental disorders. Remarkably, >1 in 4 individuals with neurodevelopmental disorders exhibit sleep rhythm disturbance. These sleep problems appear to exacerbate unruly behavior such as aggression and self-injury, making life very difficult for patients and their families. Meanwhile, numerous causative genes for monogenic neurodevelopmental disorders encode transcriptional and chromatin regulators. These observations raise fundamental questions about the relationship between sleep disturbance and neurodevelopmental conditions. Is sleep disturbance a consequence of impaired brain development or caused by dysregulation of circadian clock genes that controls daily rhythms, including the sleep/wake cycle? Do the disease-associated transcriptional regulators directly control the expression of neurodevelopmental genes, upstream clock genes, or downstream clock-target genes involved in sleep? Lack of answers to these questions limits evidence-based therapeutic strategies for impaired sleep rhythm and neurodevelopment. Model organisms are inevitable tools to establish causal roles of genes in neurodevelopment and sleep disturbance beyond genetic and clinical associations in humans. However, the laboratory mice, the primary mammalian model, are nocturnal, i.e., active during the night and tend to sleep during the day, while humans are diurnal. In addition to this chronotype difference, most inbred mouse strains do not synthesize melatonin, a key modulator of sleep and neurodevelopment. The proposed project aims to overcome these shortcomings by generating the diurnal experimental systems to interrogate the genetic mechanisms of sleep disturbance associated with impaired neurodevelopment. Our target gene is retinoic-acid induced 1 (RAI1), whose heterozygosity is responsible for Smith-Magenis Syndrome (SMS). This intellectual disability syndrome involves sleepiness during the day and elevated awakeness during the night, accompanied by inverted blood melatonin cycles. Multiple laboratories generated Rai1-mutant mice, but the mice did not exhibit sleep rhythm disturbance as seen in SMS patients. RAI1 encodes a putative histone-binding protein implicated in circadian clock gene regulation, yet the RAI1's role in neuronal circadian gene regulation remains unknown. To better understand the roles of RAI1, we will employ two approaches ― Nile grass rat, a diurnal rodent, and human neurons derived from embryonic stem cells. The proposed research will provide the first diurnal experimental systems to study SMS pathophysiology and excellent platforms to test therapeutic interventions for this condition. Numerous therapeutic agents have proven effective in nocturnal rodent models failed in human clinical trials, likely due to the chronotype difference. Thus, there is an urgent need for a diurnal experimental system, and the proposed approaches can be applied to other neurodevelopmental disorders that involve sleep disturbance and beyond.