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

Elife. 2020 Feb 19;9:e48705. doi: 10.7554/eLife.48705.


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 STXBP1 are among the most frequent causes of neurodevelopmental disorders including intellectual disabilities and epilepsies. These disorders, collectively referred to as STXBP1 encephalopathy, encompass a broad spectrum of neurologic and psychiatric features, but the pathogenesis remains elusive. Here we modeled STXBP1 encephalopathy in mice and found that Stxbp1 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 that Stxbp1 haploinsufficient mice recapitulate cardinal features of STXBP1 encephalopathy and indicate that GABAergic synaptic dysfunction is likely a crucial contributor to disease pathogenesis.

Keywords: cortical inhibitory interneurons; epilepsy; intellectual disability; mouse; neurobehaviors; neuropsychiatric dysfunctions; neuroscience; synaptic transmission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / genetics
  • Behavior, Animal
  • Body Weight / genetics
  • Brain Diseases / genetics*
  • Brain Diseases / pathology*
  • Cognition Disorders / genetics
  • Disease Models, Animal
  • Genes, Lethal
  • Haploinsufficiency*
  • Heterozygote
  • Hindlimb / physiopathology
  • Homozygote
  • Humans
  • Mice
  • Mice, Knockout
  • Munc18 Proteins / genetics*
  • Survival Rate
  • Synaptic Transmission / genetics


  • Munc18 Proteins
  • STXBP1 protein, human
  • Stxbp1 protein, mouse