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.
-
RNA-Seq analysis of Sleep deprivation in wildtype and Shank3 mutant miceNCBI Gene Expression Omnibus, GSE113754.
-
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.
Reviewing Editor
- Eunjoon Kim, Institute for Basic Science, Korea Advanced Institute of Science and Technology, Korea (South), Republic of
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
Version history
- Received: October 14, 2018
- Accepted: April 10, 2019
- Accepted Manuscript published: April 11, 2019 (version 1)
- Version of Record published: April 29, 2019 (version 2)
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.
Metrics
-
- 5,826
- views
-
- 818
- downloads
-
- 61
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Shank3 Modulates Sleep and Expression of Circadian Transcription Factors
eLife 8:e42819.
https://doi.org/10.7554/eLife.42819
Further reading
-
- Neuroscience
Vesicles within presynaptic terminals are thought to be segregated into a variety of readily releasable and reserve pools. The nature of the pools and trafficking between them is not well understood, but pools that are slow to mobilize when synapses are active are often assumed to feed pools that are mobilized more quickly, in a series. However, electrophysiological studies of synaptic transmission have suggested instead a parallel organization where vesicles within slowly and quickly mobilized reserve pools would separately feed independent reluctant- and fast-releasing subdivisions of the readily releasable pool. Here, we use FM-dyes to confirm the existence of multiple reserve pools at hippocampal synapses and a parallel organization that prevents intermixing between the pools, even when stimulation is intense enough to drive exocytosis at the maximum rate. The experiments additionally demonstrate extensive heterogeneity among synapses in the relative sizes of the slowly and quickly mobilized reserve pools, which suggests equivalent heterogeneity in the numbers of reluctant and fast-releasing readily releasable vesicles that may be relevant for understanding information processing and storage.
-
- Evolutionary Biology
- Neuroscience
Neuropeptides are ancient signaling molecules in animals but only few peptide receptors are known outside bilaterians. Cnidarians possess a large number of G protein-coupled receptors (GPCRs) – the most common receptors of bilaterian neuropeptides – but most of these remain orphan with no known ligands. We searched for neuropeptides in the sea anemone Nematostella vectensis and created a library of 64 peptides derived from 33 precursors. In a large-scale pharmacological screen with these peptides and 161 N. vectensis GPCRs, we identified 31 receptors specifically activated by 1 to 3 of 14 peptides. Mapping GPCR and neuropeptide expression to single-cell sequencing data revealed how cnidarian tissues are extensively connected by multilayer peptidergic networks. Phylogenetic analysis identified no direct orthology to bilaterian peptidergic systems and supports the independent expansion of neuropeptide signaling in cnidarians from a few ancestral peptide-receptor pairs.
