Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection

  1. Murat Kilinc
  2. Vineet Arora
  3. Thomas K Creson
  4. Camilo Rojas
  5. Aliza A Le
  6. Julie Lauterborn
  7. Brent Wilkinson
  8. Nicolas Hartel
  9. Nicholas Graham
  10. Adrian Reich
  11. Gemma Gou
  12. Yoichi Araki
  13. Àlex Bayés
  14. Marcelo Coba
  15. Gary Lynch
  16. Courtney A Miller
  17. Gavin Rumbaugh  Is a corresponding author
  1. The Scripps Research Institute, United States
  2. University of California, Irvine, United States
  3. University of Southern California, United States
  4. Institut d'Investigació Biomèdica Sant Pau, Spain
  5. Johns Hopkins School of Medicine, United States

Abstract

Loss-of-function variants in SYNGAP1 cause a developmental encephalopathy defined by cognitive impairment, autistic features, and epilepsy. SYNGAP1 splicing leads to expression of distinct functional protein isoforms. Splicing imparts multiple cellular functions of SynGAP proteins through coding of distinct C-terminal motifs. However, it remains unknown how these different splice sequences function in vivo to regulate neuronal function and behavior. Reduced expression of SynGAP-a1/2 C-terminal splice variants in mice caused severe phenotypes, including reduced survival, impaired learning, and reduced seizure latency. In contrast, upregulation of a1/2 expression improved learning and increased seizure latency. Mice expressing a1-specific mutations, which disrupted SynGAP cellular functions without altering protein expression, promoted seizure, disrupted synapse plasticity, and impaired learning. These findings demonstrate that endogenous SynGAP isoforms with a1/2 spliced sequences promote cognitive function and impart seizure protection. Regulation of SynGAP-a expression or function may be a viable therapeutic strategy to broadly improve cognitive function and mitigate seizure.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for western blots and mass spec experiments.

Article and author information

Author details

  1. Murat Kilinc

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Vineet Arora

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7856-0401
  3. Thomas K Creson

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Camilo Rojas

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Aliza A Le

    Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Julie Lauterborn

    Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Brent Wilkinson

    Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Nicolas Hartel

    Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Nicholas Graham

    Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Adrian Reich

    Bioinformatics and Statistics Core, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Gemma Gou

    Molecular Physiology of the Synapse Laboratory, Institut d'Investigació Biomèdica Sant Pau, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  12. Yoichi Araki

    Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3455-9377
  13. Àlex Bayés

    Molecular Physiology of the Synapse Laboratory, Institut d'Investigació Biomèdica Sant Pau, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5265-6306
  14. Marcelo Coba

    Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Gary Lynch

    Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Courtney A Miller

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Gavin Rumbaugh

    Departments of Neuroscience, The Scripps Research Institute, Jupiter, United States
    For correspondence
    gavin@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6360-3894

Funding

National Institute of Mental Health (MH096847 ; MH108408)

  • Gavin Rumbaugh

Autism Speaks (#10646)

  • Murat Kilinc

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 National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#15-037 and #15-038) of Scripps Florida.

Reviewing Editor

  1. Gary L Westbrook, Oregon Health and Science University, United States

Version history

  1. Received: November 19, 2021
  2. Preprint posted: December 9, 2021 (view preprint)
  3. Accepted: April 8, 2022
  4. Accepted Manuscript published: April 8, 2022 (version 1)
  5. Version of Record published: May 3, 2022 (version 2)

Copyright

© 2022, Kilinc 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. Murat Kilinc
  2. Vineet Arora
  3. Thomas K Creson
  4. Camilo Rojas
  5. Aliza A Le
  6. Julie Lauterborn
  7. Brent Wilkinson
  8. Nicolas Hartel
  9. Nicholas Graham
  10. Adrian Reich
  11. Gemma Gou
  12. Yoichi Araki
  13. Àlex Bayés
  14. Marcelo Coba
  15. Gary Lynch
  16. Courtney A Miller
  17. Gavin Rumbaugh
(2022)
Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection
eLife 11:e75707.
https://doi.org/10.7554/eLife.75707

Share this article

https://doi.org/10.7554/eLife.75707

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