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

Research output: Contribution to journalArticle

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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 - 15-03-2013

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Synaptosomal-Associated Protein 25
Dentate Gyrus
Memory Disorders
Mutation
Short-Term Memory
Phenotype
Epilepsy
Endophenotypes
Fluoxetine
Exocytosis
Valproic Acid
Amino Acid Substitution
Attention Deficit Disorder with Hyperactivity
Knockout Mice
Anticonvulsants
Antidepressive Agents
Neurotransmitter Agents
Psychiatry
Schizophrenia
Anxiety

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Ohira, Koji ; Kobayashi, Katsunori ; Toyama, Keiko ; Nakamura, Hironori K. ; Shoji, Hirotaka ; Takao, Keizo ; Takeuchi, Rika ; Yamaguchi, Shun ; Kataoka, Masakazu ; Otsuka, Shintaro ; Takahashi, Masami ; Miyakawa, Tsuyoshi. / Synaptosomal-associated protein 25 mutation induces immaturity of the dentate granule cells of adult mice. In: Molecular brain. 2013 ; Vol. 6, No. 1.
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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.",
author = "Koji Ohira and Katsunori Kobayashi and Keiko Toyama and Nakamura, {Hironori K.} and Hirotaka Shoji and Keizo Takao and Rika Takeuchi and Shun Yamaguchi and Masakazu Kataoka and Shintaro Otsuka and Masami Takahashi and Tsuyoshi Miyakawa",
year = "2013",
month = "3",
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doi = "10.1186/1756-6606-6-12",
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Ohira, K, Kobayashi, K, Toyama, K, Nakamura, HK, 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, vol. 6, no. 1, 12. https://doi.org/10.1186/1756-6606-6-12

Synaptosomal-associated protein 25 mutation induces immaturity of the dentate granule cells of adult mice. / Ohira, Koji; Kobayashi, Katsunori; Toyama, Keiko; Nakamura, Hironori K.; Shoji, Hirotaka; Takao, Keizo; Takeuchi, Rika; Yamaguchi, Shun; Kataoka, Masakazu; Otsuka, Shintaro; Takahashi, Masami; Miyakawa, Tsuyoshi.

In: Molecular brain, Vol. 6, No. 1, 12, 15.03.2013.

Research output: Contribution to journalArticle

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

PY - 2013/3/15

Y1 - 2013/3/15

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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