TY - JOUR TI - Stxbp1/Munc18-1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy AU - Chen, Wu AU - Cai, Zhao-Lin AU - Chao, Eugene S AU - Chen, Hongmei AU - Longley, Colleen M AU - Hao, Shuang AU - Chao, Hsiao-Tuan AU - Kim, Joo Hyun AU - Messier, Jessica E AU - Zoghbi, Huda Y AU - Tang, Jianrong AU - Swann, John W AU - Xue, Mingshan A2 - Monteggia, Lisa M A2 - Dulac, Catherine A2 - Missler, Markus VL - 9 PY - 2020 DA - 2020/02/19 SP - e48705 C1 - eLife 2020;9:e48705 DO - 10.7554/eLife.48705 UR - https://doi.org/10.7554/eLife.48705 AB - 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. KW - neurobehaviors KW - intellectual disability KW - epilepsy KW - neuropsychiatric dysfunctions KW - cortical inhibitory interneurons KW - synaptic transmission JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -