MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders

  1. Adam J Harrington
  2. Aram Raissi
  3. Kacey Rajkovich
  4. Stefano Berto
  5. Jaswinder Kumar
  6. Gemma Molinaro
  7. Jonathan Raduazzo
  8. Yuhong Guo
  9. Kris Loerwald
  10. Genevieve Konopka
  11. Kimberly M Huber
  12. Christopher W Cowan  Is a corresponding author
  1. Medical University of South Carolina, United States
  2. Harvard Medical School, United States
  3. The University of Texas Southwestern Medical Center, United States

Abstract

Numerous genetic variants associated with MEF2C are linked to autism, intellectual disability (ID) and schizophrenia (SCZ) - a heterogeneous collection of neurodevelopmental disorders with unclear pathophysiology. MEF2C is highly expressed in developing cortical excitatory neurons, but its role in their development remains unclear. We show here that conditional embryonic deletion of Mef2c in cortical and hippocampal excitatory neurons (Emx1-lineage) produces a dramatic reduction in cortical network activity in vivo, due in part to a dramatic increase in inhibitory and a decrease in excitatory synaptic transmission. In addition, we find that MEF2C regulates E/I synapse density predominantly as a cell-autonomous, transcriptional repressor. Analysis of differential gene expression in Mef2c mutant cortex identified a significant overlap with numerous synapse- and autism-linked genes, and the Mef2c mutant mice displayed numerous behaviors reminiscent of autism, ID and SCZ, suggesting that perturbing MEF2C function in neocortex can produce autistic- and ID-like behaviors in mice.

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The following data sets were generated

Article and author information

Author details

  1. Adam J Harrington

    Department of Neuroscience, Medical University of South Carolina, Charleston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Aram Raissi

    Department of Psychiatry, Harvard Medical School, Belmont, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kacey Rajkovich

    Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Stefano Berto

    Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jaswinder Kumar

    Department of Psychiatry, Harvard Medical School, Belmont, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Gemma Molinaro

    Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jonathan Raduazzo

    Department of Psychiatry, Harvard Medical School, Belmont, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Yuhong Guo

    Department of Psychiatry, Harvard Medical School, Belmont, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Kris Loerwald

    Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Genevieve Konopka

    Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Kimberly M Huber

    Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Christopher W Cowan

    Department of Neuroscience, Medical University of South Carolina, Charleston, United States
    For correspondence
    cowanc@musc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5472-3296

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development

  • Adam J Harrington

Simons Foundation (SFARI #206919)

  • Kimberly M Huber
  • Christopher W Cowan

National Institute on Drug Abuse

  • Christopher W Cowan

NIH Office of the Director

  • Kimberly M Huber

National Institutes of Health (F32 HD078050)

  • Adam J Harrington

National Institutes of Health (DA027664)

  • Christopher W Cowan

National Institutes of Health (HD052731)

  • Kimberly M Huber

National Institutes of Health (OD010737)

  • Christopher W Cowan

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 NIH. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2015N000178 and #2015N000160) of McLean Hospital.

Reviewing Editor

  1. Christian Rosenmund, Charité-Universitätsmedizin Berlin, Germany

Publication history

  1. Received: July 26, 2016
  2. Accepted: October 11, 2016
  3. Accepted Manuscript published: October 25, 2016 (version 1)
  4. Version of Record published: November 3, 2016 (version 2)
  5. Version of Record updated: June 27, 2017 (version 3)

Copyright

© 2016, Harrington 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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  1. Adam J Harrington
  2. Aram Raissi
  3. Kacey Rajkovich
  4. Stefano Berto
  5. Jaswinder Kumar
  6. Gemma Molinaro
  7. Jonathan Raduazzo
  8. Yuhong Guo
  9. Kris Loerwald
  10. Genevieve Konopka
  11. Kimberly M Huber
  12. Christopher W Cowan
(2016)
MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders
eLife 5:e20059.
https://doi.org/10.7554/eLife.20059

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