Editors' ChoiceAutism Spectrum Disorder

SHANK3 puts autism to sleep

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Science Translational Medicine  15 May 2019:
Vol. 11, Issue 492, eaax1714
DOI: 10.1126/scitranslmed.aax1714


Mutation of autism-associated gene SHANK3 leads to sleep problems in mice and humans.

Disruptions in social communication and language are well-known symptoms of autism spectrum disorder (ASD); however, the sleep difficulties plaguing up to 80% of people with autism are less appreciated. These sleep disturbances often correspond to a worsening of behavioral problems and are significantly disrupted to affected individuals and caregivers.

Not much is known about the cause of disrupted sleep in ASD. To investigate this issue, Ingiosi et al. examined sleep patterns in humans and mice with mutations in SHANK3, a high-confidence gene associated with autism and the neurodevelopmental disorder Phelan-McDermid Syndrome (PMS). Using records from the PMS International Registry (PMSIR), the authors verified an increase in sleep problems in patients with SHANK3 mutations versus typically developing controls. To examine the mechanisms linking SHANK3 deficiency to altered sleep, the authors performed a series of behavioral experiments using the Shank3ΔC mutant mouse model. Not only did Shank3ΔC mutants sleep less, they also took longer to fall asleep after being sleep-deprived. This corresponded to a deficit in electroencephalographic (EEG) spectra associated with deep rapid eye movement (REM) sleep. When kept in the dark, Shank3ΔC mutants showed an unusual decline in wheel running that became more disorganized over time, a behavior that indicates alteration of circadian rhythms.

To see whether changes in gene expression might provide clues as to the cause of altered sleep in Shank3ΔC mutants, the authors performed RNA sequencing on prefrontal cortex isolated from sleep-deprived mice. This revealed changes in genes involved in the MAP kinase (MAPK) signaling pathway and transcription factors that regulate circadian rhythms. The important suggestion here is that there is an identifiable molecular basis for the observed sleep disturbances. Now researchers can perform mechanistic experiments to identify which molecular pathways can be therapeutically targeted to alleviate disrupted sleep in Shank3ΔC mutants and potentially other models of ASD.

More studies will be needed to confirm the changes seen in the Shank3ΔC mouse model, and further sleep studies in patients with PMS will be important for validating the translational potential for patients. However, the insights here are an important step toward understanding the nature of disrupted sleep in ASD.

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