Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies

Neuron. 2021 Jan 6;109(1):59-72.e5. doi: 10.1016/j.neuron.2020.10.012. Epub 2020 Nov 3.


SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complex, composed of synaptobrevin, syntaxin, and SNAP25, forms the essential fusion machinery for neurotransmitter release. Recent studies have reported several mutations in the gene encoding SNAP25 as a causative factor for developmental and epileptic encephalopathies of infancy and childhood with diverse clinical manifestations. However, it remains unclear how SNAP25 mutations give rise to these disorders. Here, we show that although structurally clustered mutations in SNAP25 give rise to related synaptic transmission phenotypes, specific alterations in spontaneous neurotransmitter release are a key factor to account for disease heterogeneity. Importantly, we identified a single mutation that augments spontaneous release without altering evoked release, suggesting that aberrant spontaneous release is sufficient to cause disease in humans.

Keywords: SNAP25; child neurology; development; developmental delay; epilepsy; exocytosis; neurotransmitter; spontaneous release; synaptic transmission; synaptotagmin.

Publication types

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

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Animals
  • Brain Diseases / genetics*
  • Brain Diseases / physiopathology*
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Female
  • HEK293 Cells
  • Haploinsufficiency / genetics
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Protein Structure, Secondary
  • Rats
  • Rats, Sprague-Dawley
  • Synaptic Transmission / genetics*
  • Synaptosomal-Associated Protein 25 / chemistry
  • Synaptosomal-Associated Protein 25 / genetics*


  • SNAP25 protein, human
  • Synaptosomal-Associated Protein 25