< i > Stxbp1/Munc18-1 < /i > haploinsufficiency impairs inhibition and mediates key neurological features of < i > STXBP1 < /i > encephalopathy

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 inSTXBP1 are among the most frequent causes of neurodevelopmental disorders including intellectual disabilities and epilepsies. These disorders, collectively referred to asSTXBP1 encephalopathy, encompass a broad spectrum of neurologic and psychiatric features, but the pathogenesis remains elusive. Here we modeledSTXBP1 encephalopathy in mice and found thatStxbp1 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 thatStxbp1 haploinsufficient mice recapitulate cardinal features ofSTXBP1 encephalopathy and indicate that GABAergic synaptic dysfunction is likely a crucial contributor to disease pathogenesis.

Source: eLife - February 19, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research