An essential role for MEF2C in the cortical response to loss of sleep in mice
Abstract
Neuronal activity and gene expression in response to the loss of sleep can provide a window into the enigma of sleep function. Sleep loss is associated with brain differential gene expression, an increase in pyramidal cell mEPSC frequency and amplitude, and a characteristic rebound and resolution of slow wave sleep-slow wave activity (SWS-SWA). However, the molecular mechanism(s) mediating the sleep loss response are not well understood. We show that sleep-loss regulates MEF2C phosphorylation, a key mechanism regulating MEF2C transcriptional activity, and that MEF2C function in postnatal excitatory forebrain neurons is required for the biological events in response to sleep loss in C57BL/6J mice. These include altered gene expression, the increase and recovery of synaptic strength, and the rebound and resolution of SWS-SWA, which implicate MEF2C as an essential regulator of sleep function.
Data availability
The NCBI Gene Expression Omnibus (GEO) accession number for the RNA-seq data reported in this paper is GSE 144957
-
An essential role for MEF2C in the cortical response to loss of sleepNCBI Gene Expression Omnibus, GSE144957.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (NS103422)
- Robert W Greene
International Institute for Integrative Sleep Medicine
- Robert W Greene
National Institute of Mental Health (MH102603)
- Robert W Greene
National Institute on Deafness and Other Communication Disorders (DC014702)
- Genevieve Konopka
James S. McDonnell Foundation (220020467)
- Genevieve Konopka
National Institute on Aging (AG045795)
- Joseph S Takahashi
National Institute of Neurological Disorders and Stroke (NS106657)
- Joseph S Takahashi
Howard Hughes Medical Institute
- Joseph S Takahashi
National Institute of Mental Health (MH111464)
- Christopher W Cowan
Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD098893)
- Catherine Bridges
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Anne E West, Duke University School of Medicine, United States
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 (#102096) of the UT Southwestern Medical Center. All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.
Version history
- Received: April 27, 2020
- Accepted: August 26, 2020
- Accepted Manuscript published: August 27, 2020 (version 1)
- Version of Record published: September 14, 2020 (version 2)
Copyright
© 2020, Bjorness 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
-
- 2,762
- views
-
- 351
- downloads
-
- 22
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
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)
Further reading
-
- Genetics and Genomics
- Neuroscience
Single-cell RNA sequencing reveals the extent to which marmosets carry genetically distinct cells from their siblings.
-
- Cell Biology
- Neuroscience
Mutations in Drosophila Swiss Cheese (SWS) gene or its vertebrate orthologue Neuropathy Target Esterase (NTE) lead to progressive neuronal degeneration in flies and humans. Despite its enzymatic function as a phospholipase is well-established, the molecular mechanism responsible for maintaining nervous system integrity remains unclear. In this study, we found that NTE/SWS is present in surface glia that forms the blood-brain-barrier (BBB) and that NTE/SWS is important to maintain its structure and permeability. Importantly, BBB glia-specific expression of Drosophila NTE/SWS or human NTE in the sws mutant background fully rescues surface glial organization and partially restores BBB integrity, suggesting a conserved function of NTE/SWS. Interestingly, sws mutant glia showed abnormal organization of plasma membrane domains and tight junction rafts accompanied by the accumulation of lipid droplets, lysosomes, and multilamellar bodies. Since the observed cellular phenotypes closely resemble the characteristics described in a group of metabolic disorders known as lysosomal storage diseases (LSDs), our data established a novel connection between NTE/SWS and these conditions. We found that mutants with defective BBB exhibit elevated levels of fatty acids, which are precursors of eicosanoids and are involved in the inflammatory response. Also, as a consequence of a permeable BBB, several innate immunity factors are upregulated in an age-dependent manner, while BBB glia-specific expression of NTE/SWS normalizes inflammatory response. Treatment with anti-inflammatory agents prevents the abnormal architecture of the BBB, suggesting that inflammation contributes to the maintenance of a healthy brain barrier. Considering the link between a malfunctioning BBB and various neurodegenerative diseases, gaining a deeper understanding of the molecular mechanisms causing inflammation due to a defective BBB could help to promote the use of anti-inflammatory therapies for age-related neurodegeneration.