Stxbp1/Munc18-1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy
- Baylor College of Medicine, United States
- BCM, United States
- Texas Children's Hospital, United States
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.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
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.
Reviewing Editor
- Lisa M Monteggia, Vanderbilt University, United States
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.
Version history
- Received: May 23, 2019
- Accepted: February 18, 2020
- Accepted Manuscript published: February 19, 2020 (version 1)
- 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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Stxbp1/Munc18-1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy
eLife 9:e48705.
https://doi.org/10.7554/eLife.48705
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