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

Nobuyuki Yamasaki1234, Motoko Maekawa35, Katsunori Kobayashi36, Yasushi Kajii7, Jun Maeda8, Miho Soma5, Keizo Takao1349, Koichi Tanda134, Koji Ohira349, Keiko Toyama1349, Kouji Kanzaki7, Kohji Fukunaga10, Yusuke Sudo11, Hiroshi Ichinose113, Masashi Ikeda12133, Nakao Iwata123, Norio Ozaki133, Hidenori Suzuki6, Makoto Higuchi8, Tetsuya Suhara8, Shigeki Yuasa35 and Tsuyoshi Miyakawa114349*

Author Affiliations

1 Genetic Engineering and Functional Genomics Group, Frontier Technology Center, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan

2 Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan

3 Japan Science and Technology Agency, CREST, Saitama, Japan

4 Japan Science and Technology Agency, BIRD, Saitama, Japan

5 Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, Japan

6 Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan

7 Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama, Japan

8 Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Japan

9 Division of Systems Medicine, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Japan

10 Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai, Japan

11 Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Japan

12 Graduate School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Japan

13 Graduate School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya, Japan

14 Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Myodaiji, Okazaki, Japan

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Molecular Brain 2008, 1:6  doi:10.1186/1756-6606-1-6

Published: 10 September 2008

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.