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Here we modeled STXBP1 encephalopathy in mice and discovered that Stxbp1 haploinsufficiency caused intellectual, psychiatric, and engine dysfunctions, along with cortical hyperexcitability and seizures. Additionally, Stxbp1 haploinsufficiency reduced cortical inhibitory neurotransmission via distinct mechanisms from parvalbumin-expressing and somatostatin-expressing interneurons. These outcomes show that Stxbp1 haploinsufficient mice reca