1. Neuroscience
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Stxbp1/Munc18-1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy

  1. Wu Chen
  2. Zhao-Lin Cai
  3. Eugene S Chao
  4. Hongmei Chen
  5. Colleen M Longley
  6. Shuang Hao
  7. Hsiao-Tuan Chao
  8. Joo Hyun Kim
  9. Jessica E Messier
  10. Huda Y Zoghbi
  11. Jianrong Tang
  12. John W Swann
  13. Mingshan Xue  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. BCM, United States
  3. Texas Children's Hospital, United States
Research Article
  • Cited 2
  • Views 1,715
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Cite this article as: eLife 2020;9:e48705 doi: 10.7554/eLife.48705

Abstract

Mutations in genes encoding synaptic proteins cause many neurodevelopmental disorders, with the majority affecting postsynaptic apparatuses and much fewer in presynaptic proteins. Syntaxin-binding protein 1 (STXBP1, also known as MUNC18-1) is an essential component of the presynaptic neurotransmitter release machinery. De novo heterozygous pathogenic variants in STXBP1 are among the most frequent causes of neurodevelopmental disorders including intellectual disabilities and epilepsies. These disorders, collectively referred to as STXBP1 encephalopathy, encompass a broad spectrum of neurologic and psychiatric features, but the pathogenesis remains elusive. Here we modeled STXBP1 encephalopathy in mice and found that Stxbp1 haploinsufficiency caused cognitive, psychiatric, and motor dysfunctions, as well as cortical hyperexcitability and seizures. Furthermore, Stxbp1 haploinsufficiency reduced cortical inhibitory neurotransmission via distinct mechanisms from parvalbumin-expressing and somatostatin-expressing interneurons. These results demonstrate that Stxbp1 haploinsufficient mice recapitulate cardinal features of STXBP1 encephalopathy and indicate that GABAergic synaptic dysfunction is likely a crucial contributor to disease pathogenesis.

Article and author information

Author details

  1. Wu Chen

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7400-0519
  2. Zhao-Lin Cai

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4034-2884
  3. Eugene S Chao

    Department of Neuroscience, BCM, Houston, United States
    Competing interests
    No competing interests declared.
  4. Hongmei Chen

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  5. Colleen M Longley

    Program in Developmental Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8326-6143
  6. Shuang Hao

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    No competing interests declared.
  7. Hsiao-Tuan Chao

    Department of Pediatrics, Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2854-5470
  8. Joo Hyun Kim

    Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  9. Jessica E Messier

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5865-7043
  10. Huda Y Zoghbi

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    Huda Y Zoghbi, Senior Editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0700-3349
  11. Jianrong Tang

    Department of Pediatrics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  12. John W Swann

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8995-5812
  13. Mingshan Xue

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    For correspondence
    Mingshan.Xue@bcm.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1463-8884

Funding

Citizens United for Research in Epilepsy (CURE Epilepsy Award)

  • Mingshan Xue

National Institute of Neurological Disorders and Stroke (R01NS100893)

  • Mingshan Xue

National Institute of Mental Health (R01MH117089)

  • Mingshan Xue

Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092)

  • Huda Y Zoghbi

American Epilepsy Society (Postdoctoral Research Fellowship)

  • Wu Chen

Robert and Janice McNair Foundation (McNair MD/PhD Student Scholars)

  • Colleen M Longley

Robert and Janice McNair Foundation (McNair MD/PhD Student Scholars)

  • Jessica E Messier

National Institute of Mental Health (F30MH118804)

  • Colleen M Longley

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 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 procedures to maintain and use mice were approved in the Animal Research Protocol AN-6544 by the Institutional Animal Care and Use Committee at Baylor College of Medicine.

Reviewing Editor

  1. Lisa M Monteggia, Vanderbilt University, United States

Publication history

  1. Received: May 23, 2019
  2. Accepted: February 18, 2020
  3. Accepted Manuscript published: February 19, 2020 (version 1)
  4. Version of Record published: March 4, 2020 (version 2)

Copyright

© 2020, Chen 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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