Shank3 modulates sleep and expression of circadian transcription factors

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 <i>Shank3</i>, a high confidence ASD gene candidate, in sleep architecture and regulation. We show that mice lacking exon 21 of <i>Shank3</i> 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 <i>Per3</i>, <i>Bhlhe41</i>, <i>Hlf</i>, <i>Tef</i>, and <i>Nr1d1</i>. <i>Shank3</i> mutants also have trouble regulating wheel-running activity in constant darkness. Overall, our study shows that <i>Shank3</i> is an important modulator of sleep and clock gene expression.