Shank3 modulates sleep and expression of circadian transcription factors.

Ashley M Ingiosi,Leandro G Roser,Marcos G Frank,Dario Righelli,Elizabeth Medina,Taylor Wintler,Hannah Schoch,Kristan G Singletary,Davide Risso,Lucia Peixoto

doi:10.7554/elife.42819

Abstract

Autism Spectrum Disorder (ASD) is the most prevalent neurodevelopmental disorder in the United States and often co-presents with sleep problems. Sleep problems in ASD predict the severity of ASD core diagnostic symptoms and have a considerable impact on the quality of life of caregivers. Little is known, however, about the underlying molecular mechanisms of sleep problems in ASD. We investigated the role of Shank3, a high confidence ASD gene candidate, in sleep architecture and regulation. We show that mice lacking exon 21 of Shank3 have problems falling asleep even when sleepy. Using RNA-seq we show that sleep deprivation increases the differences in prefrontal cortex gene expression between mutants and wild types, downregulating circadian transcription factors Per3, Bhlhe41, Hlf, Tef, and Nr1d1. Shank3 mutants also have trouble regulating wheel-running activity in constant darkness. Overall, our study shows that Shank3 is an important modulator of sleep and clock gene expression.

Highlights

Autism Spectrum Disorder (ASD) is the most prevalent neurodevelopmental disorder in the United States
We show that Phelan-McDermid syndrome (PMS) patients have trouble falling and staying asleep similar to what is observed in the general ASD population
We surveyed the clinical literature to estimate the prevalence of sleep problems in ASD (Andersen et al, 2008; Cotton and Richdale, 2006; Gail Williams et al, 2004; Giannotti et al, 2008; Giannotti et al, 2006; Krakowiak et al, 2008; Liu et al, 2006; Miano et al, 2007; Paavonen et al, 2008; Polimeni et al, 2005; Richdale and Prior, 1995; Tani et al, 2003; Thirumalai et al, 2002; Wiggs and Stores, 2004) and typically developing populations (Anders and Eiben, 1997; Baweja et al, 2013; Bixler et al, 2009; Hysing et al, 2013; Leger et al, 2012; Loessl et al, 2008; Lozoff et al, 1985; Lumeng and Chervin, 2008; Ohayon et al, 2000; Pallesen et al, 2008; Patzold et al, 1998; Sadeh et al, 2000)

Summary

Introduction

Autism Spectrum Disorder (ASD) is the most prevalent neurodevelopmental disorder in the United States (diagnosed in 1 in 59 children [Baio et al, 2018]). The core symptoms of ASD include social and communication deficits, restricted interests, and repetitive behaviors (American Psychiatric Association, 2013). Several studies show that individuals with ASD report a variety of co-morbid conditions including sleep problems and altered circadian rhythms (Glickman, 2010). People with ASD have problems falling and staying asleep (Hodge et al, 2014). Sleep impairments are a strong predictor of the severity of ASD core symptoms as well as aggression and behavioral issues (Cohen et al, 2014; Tudor et al, 2012). A great number of studies documented sleep problems in ASD, little is known about the underlying molecular mechanisms

Methods

Results

Conclusion