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Molecular Brain BioMed Central - Springer · PDF fileBioMed Central Page 1 of 21 (page number not for citation purposes) Molecular Brain ... Motoko Maekawa - [email protected]; Katsunori

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    Open AcceResearchAlpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disordersNobuyuki Yamasaki1,2,3,4, Motoko Maekawa3,5, Katsunori Kobayashi3,6, Yasushi Kajii7, Jun Maeda8, Miho Soma5, Keizo Takao1,3,4,9, Koichi Tanda1,3,4, Koji Ohira3,4,9, Keiko Toyama1,3,4,9, Kouji Kanzaki7, Kohji Fukunaga10, Yusuke Sudo11, Hiroshi Ichinose3,11, Masashi Ikeda3,12,13, Nakao Iwata3,12, Norio Ozaki3,13, Hidenori Suzuki6, Makoto Higuchi8, Tetsuya Suhara8, Shigeki Yuasa3,5 and Tsuyoshi Miyakawa*1,3,4,9,14

    Address: 1Genetic Engineering and Functional Genomics Group, Frontier Technology Center, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan, 2Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan, 3Japan Science and Technology Agency, CREST, Saitama, Japan, 4Japan Science and Technology Agency, BIRD, Saitama, Japan, 5Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, Japan, 6Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan, 7Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama, Japan, 8Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Japan, 9Division of Systems Medicine, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Japan, 10Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai, Japan, 11Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Japan, 12Graduate School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Japan, 13Graduate School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya, Japan and 14Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Myodaiji, Okazaki, Japan

    Email: Nobuyuki Yamasaki - [email protected]; Motoko Maekawa - [email protected]; Katsunori Kobayashi - [email protected]; Yasushi Kajii - [email protected]; Jun Maeda - [email protected]; Miho Soma - [email protected]; Keizo Takao - [email protected]; Koichi Tanda - [email protected]; Koji Ohira - [email protected]; Keiko Toyama - [email protected]; Kouji Kanzaki - [email protected]; Kohji Fukunaga - [email protected]; Yusuke Sudo - [email protected]; Hiroshi Ichinose - [email protected]; Masashi Ikeda - [email protected]; Nakao Iwata - [email protected]; Norio Ozaki - [email protected]; Hidenori Suzuki - [email protected]; Makoto Higuchi - [email protected]; Tetsuya Suhara - [email protected]; Shigeki Yuasa - [email protected]; Tsuyoshi Miyakawa* - [email protected]

    * Corresponding author Equal contributors

    AbstractElucidating the neural and genetic factors underlying psychiatric illness is hampered by currentmethods of clinical diagnosis. The identification and investigation of clinical endophenotypes maybe one solution, but represents a considerable challenge in human subjects. Here we report thatmice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependentprotein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impairedneuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severeworking memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seenin schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis ofthe hippocampus of these mutants revealed that the expression levels of more than 2000 genes

    Published: 10 September 2008

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

    Received: 12 August 2008Accepted: 10 September 2008

    This article is available from: http://www.molecularbrain.com/content/1/1/6

    2008 Yamasaki et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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    were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highlyselective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG wasincreased by more than 50 percent, the number of mature neurons in the DG was dramaticallydecreased. Morphological and physiological features of the DG neurons in the mutants werestrikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expressionin 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 themutant mice were used to classify individuals into two clusters, one of which contained 16 of 18schizophrenic 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, wepropose that an "immature DG" in adulthood might induce alterations in behavior and serve as apromising candidate endophenotype of schizophrenia and other human psychiatric disorders.

    BackgroundElucidating the neural and genetic factors underlying psy-chiatric illness is hampered by the current methods ofclinical diagnosis [1]. The identification and investigationof clinical endophenotypes might be one solution [2], butrepresents a considerable challenge in human subjects.Therefore, establishing animal models of psychiatric dis-orders is essential for understanding the pathogenesis/pathophysiology of the disorders [3-6]. Previously, wereported that forebrain-specific calcineurin (CN) knock-out mice have severe working/episodic-like memory defi-cits [7], and exhibit multiple abnormal behaviors relatedto schizophrenia [8]. Schizophrenia is significantly associ-ated with a variation in the 8p21.3 gene, PPP3CC, whichencodes the CNA gamma subunit of calcineurin [9-11].Based on these findings, we speculated that we could effi-ciently obtain a mouse model of psychiatric disorders byapplying a comprehensive behavioral test battery [12] tovarious strains of mice bearing mutations of the genesencoding the molecules involved in CN signaling path-ways or CN related neural mechanisms [13]. We assessedseven different strains of mutant mice: mice lacking type3 isoform ryanodine receptor, neuronal nitric oxide syn-thase, adenomatous polyposis coli, calcium/calmodulin-dependent protein kinase IV, pituitary adenylate cyclase-activated polypeptide, nuclear factor of activated T cellsc2/c3/c4 [14] or alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII). Four strainsexhibited increased locomotor activity, and three strainsexhibited abnormal social behavior (Miyakawa, unpub-lished observations). Among them, the only mutantmouse strain that exhibited a significant working memorydeficit, a proposed functional endophenotype of schizo-phrenia and other psychiatric disorders [15], was hetero-zygous for a null mutation of the alpha-isoform ofCaMKII (alpha-CaMKII+/-) (Figure 1A and 1B). CaMKII isa ubiquitous serine/threonine protein kinase that is abun-dant in the brain (up to 2% of the total protein); a holoen-zyme that consists of four isozymes (, , , );phosphorylates protein substrates, such as AMPA recep-

    tors, synapsin I, tyrosine hydroxylase, L-type Ca2+ chan-nels, and MAP-2, and itself by autophosphorylation; andis important for long-term potentiation, synaptic plastic-ity, and memory formation [16-18]. CaMKII is situateddownstream of CN in a model [19].

    Here we report that alpha-CaMKII+/- mice have pro-foundly dysregulated behaviors and impaired neuronaldevelopment in the DG. The behavioral abnormalitiesinclude a severe working memory deficit and an exagger-ated infradian rhythm, which are similar to symptomsseen in schizophrenia and other psychiatric disorders.Transcriptome analysis of the hippocampus of thesemutants revealed that the expression levels of more than2000 genes were significantly changed. Strikingly, amongthe 20 most downregulated genes, 5 had highly selectiveexpression in the DG. Whereas BrdU incorporated cells inthe mutant mouse DG was increased by more than 50 per-cent, the number of mature neurons in the DG was dra-matically decreased. Morphological and physiologicalfeatures of the DG neurons in the mutants were strikinglysimilar to those of immature DG neurons in normalrodents. Statistical clustering of human post-mortembrains using 10 genes differentially-expressed in themutant mice were used to classify individuals into twoclusters, one of which contained 16 of 18 schizophrenicpatients. Nearly half of the differentially-expressed probesin the schizophrenia-enriched cluster encoded genes thatare involved in neurogenesis or in neuronal migration/maturation. Based on these results, we propose that an"immature DG" in adulthood might induc

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