title: Synaptosomal-associated protein 25 mutation induces immaturity of the dentate granule cells of adult mice.
abstract: 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.
authors.affiliation: Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, 470-1192, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ohira
authors.forename: Katsunori
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Keiko
authors.initials: K
authors.lastname: Toyama
authors.forename: Hironori K
authors.initials: HK
authors.lastname: Nakamura
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Shoji
authors.forename: Keizo
authors.initials: K
authors.lastname: Takao
authors.forename: Rika
authors.initials: R
authors.lastname: Takeuchi
authors.forename: Shun
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kataoka
authors.forename: Shintaro
authors.initials: S
authors.lastname: Otsuka
authors.forename: Masami
authors.initials: M
authors.lastname: Takahashi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics; D018891:Dentate Gyrus / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology*; D020869:Gene Expression Profiling; D055879:Gene Knock-In Techniques; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics*; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; C092069:activity regulated cytoskeletal-associated protein; D014635:Valproic Acid