A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse

Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2431-6. doi: 10.1073/pnas.0610222104. Epub 2007 Feb 5.

Abstract

The neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is essential for synaptic vesicle exocytosis, but its study has been limited by the neonatal lethality of murine SNARE knockouts. Here, we describe a viable mouse line carrying a mutation in the b-isoform of neuronal SNARE synaptosomal-associated protein of 25 kDa (SNAP-25). The causative I67T missense mutation results in increased binding affinities within the SNARE complex, impaired exocytotic vesicle recycling and granule exocytosis in pancreatic beta-cells, and a reduction in the amplitude of evoked cortical excitatory postsynaptic potentials. The mice also display ataxia and impaired sensorimotor gating, a phenotype which has been associated with psychiatric disorders in humans. These studies therefore provide insights into the role of the SNARE complex in both diabetes and psychiatric disease.

MeSH terms

  • Alcoholic Intoxication
  • Animals
  • Ataxia / genetics*
  • Diabetes Mellitus / etiology
  • Exocytosis / genetics*
  • Gait Disorders, Neurologic / genetics*
  • Genes, Dominant
  • Insulin-Secreting Cells
  • Mental Disorders / etiology
  • Mice
  • Mice, Mutant Strains
  • Models, Animal
  • Mutation, Missense*
  • SNARE Proteins / physiology
  • Synaptic Vesicles / genetics*
  • Synaptosomal-Associated Protein 25 / genetics*
  • Synaptosomal-Associated Protein 25 / physiology

Substances

  • SNARE Proteins
  • Synaptosomal-Associated Protein 25