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

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.