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

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 <i>STXBP1</i> are among the most frequent causes of neurodevelopmental disorders including intellectual disabilities and epilepsies. These disorders, collectively referred to as <i>STXBP1</i> encephalopathy, encompass a broad spectrum of neurologic and psychiatric features, but the pathogenesis remains elusive. Here we modeled <i>STXBP1</i> encephalopathy in mice and found that <i>Stxbp1</i> haploinsufficiency caused cognitive, psychiatric, and motor dysfunctions, as well as cortical hyperexcitability and seizures. Furthermore, <i>Stxbp1</i> haploinsufficiency reduced cortical inhibitory neurotransmission via distinct mechanisms from parvalbumin-expressing and somatostatin-expressing interneurons. These results demonstrate that <i>Stxbp1</i> haploinsufficient mice recapitulate cardinal features of <i>STXBP1</i> encephalopathy and indicate that GABAergic synaptic dysfunction is likely a crucial contributor to disease pathogenesis.