Stxbp1/Munc18-1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy
| Autor: | Huda Y. Zoghbi, Jessica E Messier, John W. Swann, Eugene S. Chao, Jianrong Tang, Hsiao-Tuan Chao, Zhao-Lin Cai, Mingshan Xue, Shuang Hao, Joo Hyun Kim, Hongmei Chen, Wu Chen, Colleen M Longley |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Mouse QH301-705.5 Science Encephalopathy Neurotransmission Inhibitory postsynaptic potential General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound Epilepsy 0302 clinical medicine Postsynaptic potential neurobehaviors STXBP1 Medicine synaptic transmission Biology (General) Neurotransmitter General Immunology and Microbiology business.industry General Neuroscience General Medicine medicine.disease 030104 developmental biology chemistry intellectual disability epilepsy cortical inhibitory interneurons business Haploinsufficiency Neuroscience 030217 neurology & neurosurgery Research Article neuropsychiatric dysfunctions |
| Zdroj: | eLife eLife, Vol 9 (2020) |
| ISSN: | 2050-084X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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