Shank3 Modulates Sleep and Expression of Circadian Transcription Factors
- Washington State University, United States
- National Research Council (CNR), Italy
- University of Padova, Italy
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.
Data availability
Sequencing data have been deposited in GEO under accession code GSE113754. Source data files have been provided for Figures 1-4, Tables 1 and 2 and Supplementary Files 1 and 2. The R code used in this article is available on GitHub (github.com/drighelli/peixoto). The R code used for the statistical analysis of RNA-seq and circadian wheel running data is also available in Source Code file 1.
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RNA-Seq analysis of Sleep deprivation in wildtype and Shank3 mutant miceNCBI Gene Expression Omnibus, GSE113754.
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Gene expression linked to sleep homeostasis in murine cortexNCBI Gene Expression Omnibus, GSE78215.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (K01NS104172)
- Lucia Peixoto
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of Washington State University. Protocol numbers: 04705-001 and 04704-001IACUC 6155-Peixoto BreedingIACUC 4705-Peixoto experimentalIACUC 4581-Frank experimental
Human subjects: PMSIR patient data was obtained de-identified under IRB exemption 15005-Peixoto
Copyright
© 2019, Ingiosi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Shank3 Modulates Sleep and Expression of Circadian Transcription Factors
eLife 8:e42819.
https://doi.org/10.7554/eLife.42819
Further reading
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The role of cerebellum in controlling eye movements is well established, but its contribution to more complex forms of visual behavior has remained elusive. To study cerebellar activity during visual attention we recorded extracellular activity of dentate nucleus (DN) neurons in two non-human primates (NHPs). NHPs were trained to read the direction indicated by a peripheral visual stimulus while maintaining fixation at the center, and report the direction of the cue by performing a saccadic eye movement into the same direction following a delay. We found that single-unit DN neurons modulated spiking activity over the entire time course of the task, and that their activity often bridged temporally separated intra-trial events, yet in a heterogeneous manner. To better understand the heterogeneous relationship between task structure, behavioral performance, and neural dynamics, we constructed a behavioral, an encoding, and a decoding model. Both NHPs showed different behavioral strategies, which influenced the performance. Activity of the DN neurons reflected the unique strategies, with the direction of the visual stimulus frequently being encoded long before an upcoming saccade. Moreover, the latency of the ramping activity of DN neurons following presentation of the visual stimulus was shorter in the better performing NHP. Labeling with the retrograde tracer Cholera Toxin B in the recording location in the DN indicated that these neurons predominantly receive inputs from Purkinje cells in the D1 and D2 zones of the lateral cerebellum as well as neurons of the principal olive and medial pons, all regions known to connect with neurons in the prefrontal cortex contributing to planning of saccades. Together, our results highlight that DN neurons can dynamically modulate their activity during a visual attention task, comprising not only sensorimotor but also cognitive attentional components.
