Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior

  1. Thomas K Creson
  2. Camilo Rojas
  3. Ernie Hwaun
  4. Thomas Vaissiere
  5. Murat Kilinc
  6. Andres Jimenez-Gomez
  7. J Lloyd Holder
  8. Jianrong Tang
  9. Laura L Colgin
  10. Courtney A Miller
  11. Gavin Rumbaugh  Is a corresponding author
  1. The Scripps Research Institute, United States
  2. University of Texas at Austin, United States
  3. Baylor College of Medicine, United States

Abstract

It remains unclear to what extent neurodevelopmental disorder (NDD) risk genes retain functions into adulthood and how they may influence disease phenotypes. SYNGAP1 haploinsufficiency causes a severe NDD defined by autistic traits, cognitive impairment, and epilepsy. To determine if this gene retains therapeutically-relevant biological functions into adulthood, we performed a gene restoration technique in a mouse model for SYNGAP1 haploinsufficiency. Adult restoration of SynGAP protein improved behavioral and electrophysiological measures of memory and seizure. This included the elimination of interictal events that worsened during sleep. These events may be a biomarker for generalized cortical dysfunction in SYNGAP1 disorders because they also worsened during sleep in the human patient population. We conclude that SynGAP protein retains biological functions throughout adulthood and that non-developmental functions may contribute to disease phenotypes. Thus, treatments that target debilitating aspects of severe NDDs, such as medically-refractory seizures and cognitive impairment, may be effective in adult patients.

Data availability

Data used for generating figures are included in the manuscript and supporting files.

Article and author information

Author details

  1. Thomas K Creson

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    No competing interests declared.
  2. Camilo Rojas

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    No competing interests declared.
  3. Ernie Hwaun

    Institute for Neuroscience, University of Texas at Austin, Austin, United States
    Competing interests
    No competing interests declared.
  4. Thomas Vaissiere

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    No competing interests declared.
  5. Murat Kilinc

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    No competing interests declared.
  6. Andres Jimenez-Gomez

    Department of Pediatrics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  7. J Lloyd Holder

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

    Department of Pediatrics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  9. Laura L Colgin

    Center for Learning and Memory, University of Texas at Austin, Austin, United States
    Competing interests
    Laura L Colgin, Reviewing editor, eLife.
  10. Courtney A Miller

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    No competing interests declared.
  11. Gavin Rumbaugh

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    For correspondence
    grumbaug@scripps.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6360-3894

Funding

National Institute of Mental Health (MH108408)

  • Gavin Rumbaugh

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experiments were conducted according to protocols submitted to, and approved by, Scripps Research (Protocol #15-037 and #15-038) and the Baylor College of Medicine (Protocol #AN5585) Institutional Animal Care and Use Committees.

Human subjects: The SYNGAP1 Patient Registry [42] (https://syngap1registry.iamrare.org) is funded through the National Organization of Rare Disorders. Collection of human subject data was reviewed and approved by Hummingbird (Study # 2016-57-SYNGAP) and Baylor College of Medicine (Study #H-30480 and #H-41411) Institutional Review Boards.The parents of patients S3-060 and S3-080, which are distinct patients from those represented in Supplemental Table 4, provided written informed consent according to a protocol approved by the Baylor College of Medicine Institutional Review Board.

Reviewing Editor

  1. Gary L Westbrook, Vollum Institute, United States

Version history

  1. Received: March 15, 2019
  2. Accepted: April 15, 2019
  3. Accepted Manuscript published: April 26, 2019 (version 1)
  4. Version of Record published: May 7, 2019 (version 2)

Copyright

© 2019, Creson 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. Thomas K Creson
  2. Camilo Rojas
  3. Ernie Hwaun
  4. Thomas Vaissiere
  5. Murat Kilinc
  6. Andres Jimenez-Gomez
  7. J Lloyd Holder
  8. Jianrong Tang
  9. Laura L Colgin
  10. Courtney A Miller
  11. Gavin Rumbaugh
(2019)
Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior
eLife 8:e46752.
https://doi.org/10.7554/eLife.46752

Share this article

https://doi.org/10.7554/eLife.46752

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