Synaptosomal-associated protein 25 mutation induces immaturity of the dentate granule cells of adult mice

Mol Brain. 2013 Mar 12:6:12. doi: 10.1186/1756-6606-6-12.


Background: Synaptosomal-associated protein, 25 kDa (SNAP-25) regulates the exocytosis of neurotransmitters. Growing evidence suggests that SNAP-25 is involved in neuropsychiatric disorders, such as schizophrenia, attention-deficit/hyperactivity disorder, and epilepsy. Recently, increases in anxiety-related behaviors and epilepsy have been observed in SNAP-25 knock-in (KI) mice, which have a single amino acid substitution of Ala for Ser187. However, the molecular and cellular mechanisms underlying the abnormalities in this mutant remain unknown.

Results: In this study, we found that a significant number of dentate gyrus (DG) granule cells was histologically and electrophysiologically similar to immature DG neurons in the dentate gyrus of the adult mutants, a phenomenon termed the "immature DG" (iDG). SNAP-25 KI mice and other mice possessing the iDG phenotype, i.e., alpha-calcium/calmodulin-dependent protein kinase II heterozygous mice, Schnurri-2 knockout mice, and mice treated with the antidepressant fluoxetine, showed similar molecular expression patterns, with over 100 genes similarly altered. A working memory deficit was also identified in mutant mice during a spontaneous forced alternation task using a modified T-maze, a behavioral task known to be dependent on hippocampal function. Chronic treatments with the antiepileptic drug valproate abolished the iDG phenotype and the working memory deficit in mutants.

Conclusions: These findings suggest that the substitution of Ala for Ser187 in SNAP-25 induces the iDG phenotype, which can also be caused by epilepsy, and led to a severe working memory deficit. In addition, the iDG phenotype in adulthood is likely an endophenotype for at least a part of some common psychiatric disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects
  • Aging / metabolism
  • Aging / pathology*
  • Animals
  • Biomarkers / metabolism
  • Cytoskeletal Proteins / genetics
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / growth & development*
  • Dentate Gyrus / pathology*
  • Gene Expression Profiling
  • Gene Knock-In Techniques
  • Memory, Short-Term / drug effects
  • Mice
  • Mice, Mutant Strains
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics
  • Neurogenesis / drug effects
  • Neurogenesis / genetics
  • Phenotype
  • Promoter Regions, Genetic / genetics
  • Synaptosomal-Associated Protein 25 / genetics*
  • Valproic Acid / pharmacology


  • Biomarkers
  • Cytoskeletal Proteins
  • Nerve Tissue Proteins
  • Snap25 protein, mouse
  • Synaptosomal-Associated Protein 25
  • activity regulated cytoskeletal-associated protein
  • Valproic Acid