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Stxbp1/Munc18-1 haploinsufficiency in mice recapitulates key features of STXBP1 encephalopathy and impairs cortical inhibition

Wu Chen, Zhao-Lin Cai, Eugene S. Chao, Hongmei Chen, Shuang Hao, Hsiao-Tuan Chao, Joo Hyun Kim, Jessica E. Messier, Huda Y. Zoghbi, Jianrong Tang, John W. Swann, View ORCID ProfileMingshan Xue
doi: https://doi.org/10.1101/621516
Wu Chen
Department of Neuroscience, Baylor College of Medicine, Houston Texas, 77030, USAThe Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston Texas, 77030, USA
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Zhao-Lin Cai
Department of Neuroscience, Baylor College of Medicine, Houston Texas, 77030, USAThe Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston Texas, 77030, USA
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Eugene S. Chao
Department of Neuroscience, Baylor College of Medicine, Houston Texas, 77030, USAThe Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston Texas, 77030, USA
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Hongmei Chen
Department of Neuroscience, Baylor College of Medicine, Houston Texas, 77030, USAThe Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston Texas, 77030, USA
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Shuang Hao
Department of Pediatrics, Baylor College of Medicine, Houston Texas, 77030, USAJan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston Texas, 77030, USA
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Hsiao-Tuan Chao
Department of Pediatrics, Baylor College of Medicine, Houston Texas, 77030, USAJan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston Texas, 77030, USADepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston Texas, 77030, USA
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Joo Hyun Kim
Department of Neuroscience, Baylor College of Medicine, Houston Texas, 77030, USAThe Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston Texas, 77030, USA
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Jessica E. Messier
Department of Neuroscience, Baylor College of Medicine, Houston Texas, 77030, USAThe Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston Texas, 77030, USA
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Huda Y. Zoghbi
Department of Neuroscience, Baylor College of Medicine, Houston Texas, 77030, USADepartment of Pediatrics, Baylor College of Medicine, Houston Texas, 77030, USAJan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston Texas, 77030, USADepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston Texas, 77030, USAHoward Hughes Medical Institute, Baylor College of Medicine, Houston Texas, 77030, USA
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Jianrong Tang
Department of Pediatrics, Baylor College of Medicine, Houston Texas, 77030, USAJan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston Texas, 77030, USA
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John W. Swann
Department of Neuroscience, Baylor College of Medicine, Houston Texas, 77030, USAThe Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston Texas, 77030, USADepartment of Pediatrics, Baylor College of Medicine, Houston Texas, 77030, USA
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Mingshan Xue
Department of Neuroscience, Baylor College of Medicine, Houston Texas, 77030, USAThe Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston Texas, 77030, USADepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston Texas, 77030, USA
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  • ORCID record for Mingshan Xue
  • For correspondence: mxue@bcm.edu
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Abstract

Mutations in genes encoding synaptic proteins cause many neurodevelopmental disorders, but the underlying pathogeneses are poorly understood. Syntaxin-binding protein 1 (STXBP1) is an essential component of the neurotransmitter release machinery. Its de novo heterozygous mutations are among the most frequent causes of neurodevelopmental disorders including intellectual disabilities and epilepsies. These disorders, collectively referred to as STXBP1 encephalopathy, affect a broad spectrum of neurological and neuropsychiatric features common among neurodevelopmental disorders. To gain insight into STXBP1 encephalopathy pathogenesis, we generated new Stxbp1 null alleles in mice and found that Stxbp1 haploinsufficiency impaired cognitive, psychiatric, and motor functions and caused cortical hyperexcitability and seizures. Surprisingly, Stxbp1 haploinsufficiency reduced neurotransmission from cortical parvalbumin- and somatostatin-expressing GABAergic interneurons by differentially decreasing the synaptic strength and connectivity, respectively. These results demonstrate that Stxbp1 haploinsufficient mice recapitulate key features of STXBP1 encephalopathy and indicate that inhibitory dysfunction is likely a key contributor to the disease pathogenesis.

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Posted April 29, 2019.
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Stxbp1/Munc18-1 haploinsufficiency in mice recapitulates key features of STXBP1 encephalopathy and impairs cortical inhibition
Wu Chen, Zhao-Lin Cai, Eugene S. Chao, Hongmei Chen, Shuang Hao, Hsiao-Tuan Chao, Joo Hyun Kim, Jessica E. Messier, Huda Y. Zoghbi, Jianrong Tang, John W. Swann, Mingshan Xue
bioRxiv 621516; doi: https://doi.org/10.1101/621516
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Stxbp1/Munc18-1 haploinsufficiency in mice recapitulates key features of STXBP1 encephalopathy and impairs cortical inhibition
Wu Chen, Zhao-Lin Cai, Eugene S. Chao, Hongmei Chen, Shuang Hao, Hsiao-Tuan Chao, Joo Hyun Kim, Jessica E. Messier, Huda Y. Zoghbi, Jianrong Tang, John W. Swann, Mingshan Xue
bioRxiv 621516; doi: https://doi.org/10.1101/621516

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