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

Koji Ohira, Katsunori Kobayashi, Keiko Toyama, Hironori K. Nakamura, Hirotaka Shoji, Keizo Takao, Rika Takeuchi, Shun Yamaguchi, Masakazu Kataoka, Shintaro Otsuka, Masami Takahashi, Tsuyoshi Miyakawa

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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.

Original languageEnglish
Article number12
JournalMolecular brain
Volume6
Issue number1
DOIs
Publication statusPublished - 2013

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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    Ohira, K., Kobayashi, K., Toyama, K., Nakamura, H. K., Shoji, H., Takao, K., Takeuchi, R., Yamaguchi, S., Kataoka, M., Otsuka, S., Takahashi, M., & Miyakawa, T. (2013). Synaptosomal-associated protein 25 mutation induces immaturity of the dentate granule cells of adult mice. Molecular brain, 6(1), [12]. https://doi.org/10.1186/1756-6606-6-12