Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders.

Nobuyuki Yamasaki, Motoko Maekawa, Katsunori Kobayashi, Yasushi Kajii, Jun Maeda, Miho Soma, Keizo Takao, Koichi Tanda, Koji Ohira, Keiko Toyama, Kouji Kanzaki, Kohji Fukunaga, Yusuke Sudo, Hiroshi Ichinose, Masashi Ikeda, Nakao Iwata, Norio Ozaki, Hidenori Suzuki, Makoto Higuchi, Tetsuya Suhara & 2 others Shigeki Yuasa, Tsuyoshi Miyakawa

Research output: Contribution to journalArticle

172 Citations (Scopus)

Abstract

Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders.

Original languageEnglish
Number of pages1
JournalMolecular brain
Volume1
DOIs
Publication statusPublished - 01-01-2008

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Endophenotypes
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Dentate Gyrus
Psychiatry
Neurons
Schizophrenia
Genes
Calbindins
Calcium-Calmodulin-Dependent Protein Kinases
Neurogenesis
Memory Disorders
Gene Expression Profiling
Bromodeoxyuridine
Multigene Family
Mood Disorders
Bipolar Disorder
Short-Term Memory
Cluster Analysis
Rodentia
Hippocampus

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Yamasaki, Nobuyuki ; Maekawa, Motoko ; Kobayashi, Katsunori ; Kajii, Yasushi ; Maeda, Jun ; Soma, Miho ; Takao, Keizo ; Tanda, Koichi ; Ohira, Koji ; Toyama, Keiko ; Kanzaki, Kouji ; Fukunaga, Kohji ; Sudo, Yusuke ; Ichinose, Hiroshi ; Ikeda, Masashi ; Iwata, Nakao ; Ozaki, Norio ; Suzuki, Hidenori ; Higuchi, Makoto ; Suhara, Tetsuya ; Yuasa, Shigeki ; Miyakawa, Tsuyoshi. / Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders. In: Molecular brain. 2008 ; Vol. 1.
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Yamasaki, N, Maekawa, M, Kobayashi, K, Kajii, Y, Maeda, J, Soma, M, Takao, K, Tanda, K, Ohira, K, Toyama, K, Kanzaki, K, Fukunaga, K, Sudo, Y, Ichinose, H, Ikeda, M, Iwata, N, Ozaki, N, Suzuki, H, Higuchi, M, Suhara, T, Yuasa, S & Miyakawa, T 2008, 'Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders.', Molecular brain, vol. 1. https://doi.org/10.1186/1756-6606-1-6

Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders. / Yamasaki, Nobuyuki; Maekawa, Motoko; Kobayashi, Katsunori; Kajii, Yasushi; Maeda, Jun; Soma, Miho; Takao, Keizo; Tanda, Koichi; Ohira, Koji; Toyama, Keiko; Kanzaki, Kouji; Fukunaga, Kohji; Sudo, Yusuke; Ichinose, Hiroshi; Ikeda, Masashi; Iwata, Nakao; Ozaki, Norio; Suzuki, Hidenori; Higuchi, Makoto; Suhara, Tetsuya; Yuasa, Shigeki; Miyakawa, Tsuyoshi.

In: Molecular brain, Vol. 1, 01.01.2008.

Research output: Contribution to journalArticle

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T1 - Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders.

AU - Yamasaki, Nobuyuki

AU - Maekawa, Motoko

AU - Kobayashi, Katsunori

AU - Kajii, Yasushi

AU - Maeda, Jun

AU - Soma, Miho

AU - Takao, Keizo

AU - Tanda, Koichi

AU - Ohira, Koji

AU - Toyama, Keiko

AU - Kanzaki, Kouji

AU - Fukunaga, Kohji

AU - Sudo, Yusuke

AU - Ichinose, Hiroshi

AU - Ikeda, Masashi

AU - Iwata, Nakao

AU - Ozaki, Norio

AU - Suzuki, Hidenori

AU - Higuchi, Makoto

AU - Suhara, Tetsuya

AU - Yuasa, Shigeki

AU - Miyakawa, Tsuyoshi

PY - 2008/1/1

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N2 - Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders.

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