TY - JOUR
T1 - Synaptosomal-associated protein 25 mutation induces immaturity of the dentate granule cells of adult mice
AU - Ohira, Koji
AU - Kobayashi, Katsunori
AU - Toyama, Keiko
AU - Nakamura, Hironori K.
AU - Shoji, Hirotaka
AU - Takao, Keizo
AU - Takeuchi, Rika
AU - Yamaguchi, Shun
AU - Kataoka, Masakazu
AU - Otsuka, Shintaro
AU - Takahashi, Masami
AU - Miyakawa, Tsuyoshi
N1 - Funding Information:
We would like to thank Satoko Noma for assisting us with the immunostaining and quantifications. This work was supported by KAKENHI (Grant-in-Aid for Scientific Research) on Young Scientists (A) (16680015), Scientific Research (B) (21300121), and Exploratory Research (19653081) from the Ministry of Education, Science, Sports, and Culture of Japan from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, a grant from the Neuroinformatics Japan Center (NIJC), CREST of Japan Science and Technology Agency (JST), and the NEXT program.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
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U2 - 10.1186/1756-6606-6-12
DO - 10.1186/1756-6606-6-12
M3 - Article
C2 - 23497716
AN - SCOPUS:84874793864
SN - 1756-6606
VL - 6
JO - Molecular brain
JF - Molecular brain
IS - 1
M1 - 12
ER -