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

Abstract

150 words) 21 Mutations in genes encoding synaptic proteins cause many neurodevelopmental disorders, but 22 the underlying pathogeneses are poorly understood. Syntaxin-binding protein 1 (STXBP1) is an 23 essential component of the neurotransmitter release machinery. Its de novo heterozygous 24 mutations are among the most frequent causes of neurodevelopmental disorders including 25 intellectual disabilities and epilepsies. These disorders, collectively referred to as STXBP1 26 encephalopathy, affect a broad spectrum of neurological and neuropsychiatric features common 27 among neurodevelopmental disorders. To gain insight into STXBP1 encephalopathy 28 pathogenesis, we generated new Stxbp1 null alleles in mice and found that Stxbp1 29 haploinsufficiency impaired cognitive, psychiatric, and motor functions and caused cortical 30 hyperexcitability and seizures. Surprisingly, Stxbp1 haploinsufficiency reduced 31 neurotransmission from cortical parvalbumin-and somatostatin-expressing GABAergic 32 interneurons by differentially decreasing the synaptic strength and connectivity, respectively. 33 These results demonstrate that Stxbp1 haploinsufficient mice recapitulate key features of 34