MeCP2 in cholinergic interneurons of nucleus accumbens regulates fear learning
- Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, China
- Sir Run Run Shaw Hospital, China
Abstract
Methyl-CpG-binding protein 2 (MeCP2) encoded by the MECP2 gene is a transcriptional regulator whose mutations cause Rett syndrome (RTT). Mecp2-deficient mice show fear regulation impairment; however, the cellular and molecular mechanisms underlying this abnormal behavior are largely uncharacterized. Here, we showed that Mecp2 gene deficiency in cholinergic interneurons of the nucleus accumbens (NAc) dramatically impaired fear learning. We further found that spontaneous activity of cholinergic interneurons in Mecp2-deficient mice decreased, mediated by enhanced inhibitory transmission via α2-containing GABAA receptors. With MeCP2 restoration, opto- and chemo-genetic activation, and RNA interference in ChAT-expressing interneurons of the NAc, impaired fear retrieval was rescued. Taken together, these results reveal a previously unknown role of MeCP2 in NAc cholinergic interneurons in fear regulation, suggesting that modulation of neurons in the NAc may ameliorate fear-related disorders.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3, 4, 5 and 6.
Article and author information
Author details
Funding
The National Key Research and Development Plan of Ministry of Science and Technology of China (2016YF051000)
- Xiao-Ming Li
Key Project of the National Natural Science Foundation of China (31430034)
- Xiao-Ming Li
Science and Technology Program of Guangdong (2018B030334001)
- Xiao-Ming Li
Key Realm R&D Prgram of Guangdong Province (2019B030335001)
- Xiao-Ming Li
Funds for Creative Research Groups of China from the National Natural Science Foundation of China (81521062)
- Xiao-Ming Li
Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (2019PT310023)
- Xiao-Ming Li
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Mary Kay Lobo, University of Maryland, United States
Ethics
Animal experimentation: Mouse care and use followed the guidelines of the Animal Advisory Committee at Zhejiang University and the US National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. The care and use of the mice in this work were reviewed and approved by the Animal Advisory Committee at Zhejiang University (ZJU201553001). Every effort was made to minimize suffering.
Version history
- Received: January 21, 2020
- Accepted: May 18, 2020
- Accepted Manuscript published: May 18, 2020 (version 1)
- Version of Record published: May 29, 2020 (version 2)
Copyright
© 2020, Zhang 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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MeCP2 in cholinergic interneurons of nucleus accumbens regulates fear learning
eLife 9:e55342.
https://doi.org/10.7554/eLife.55342
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