Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett Syndrome

Abstract

The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2+/- mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome.

Article and author information

Author details

  1. Kerstin Ure

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  2. Hui Lu

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  3. Wei Wang

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  4. Aya Ito-Ishida

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  5. Zhenyu Wu

    Department of Pediatrics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  6. Ling-jie He

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  7. Yehezkel Sztainberg

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  8. Wu Chen

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  9. Jianrong Tang

    Department of Pediatrics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  10. Huda Y Zoghbi

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    For correspondence
    hzoghbi@bcm.edu
    Competing interests
    Huda Y Zoghbi, Senior editor, eLife.

Reviewing Editor

  1. Catherine Dulac, Howard Hughes Medical Institute, Harvard University, United States

Ethics

Animal experimentation: All mouse care and manipulation was approved by the Baylor College of Medicine Institutional Animal Care and Use Committee (IACUC, Protocol AN-1013). Every effort was made to minimize suffering.

Version history

  1. Received: January 4, 2016
  2. Accepted: June 9, 2016
  3. Accepted Manuscript published: June 21, 2016 (version 1)
  4. Version of Record published: July 15, 2016 (version 2)

Copyright

© 2016, Ure 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. Kerstin Ure
  2. Hui Lu
  3. Wei Wang
  4. Aya Ito-Ishida
  5. Zhenyu Wu
  6. Ling-jie He
  7. Yehezkel Sztainberg
  8. Wu Chen
  9. Jianrong Tang
  10. Huda Y Zoghbi
(2016)
Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett Syndrome
eLife 5:e14198.
https://doi.org/10.7554/eLife.14198

Share this article

https://doi.org/10.7554/eLife.14198

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