統合失調症のカルシニューリン仮説に基づいた統合失調症発症メカニズムの解明

• Project/Area Number: 20023017
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Fujita Health University (2009); Kyoto University (2008)
• Principal Investigator: 宮川 剛 Fujita Health University, 総合医科学研究所, 教授 (10301780)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥7,600,000 (Direct Cost: ¥7,600,000); Fiscal Year 2009: ¥3,800,000 (Direct Cost: ¥3,800,000); Fiscal Year 2008: ¥3,800,000 (Direct Cost: ¥3,800,000)
• Keywords: 統合失調症 / カルシニューリン / 遺伝子改変マウス / 網羅的行動テストバッテリー / 精神疾患 / 未成熟な歯状回

Research Abstract

カルシニューリン(CN)の前脳特異的欠損マウスは統合失調症様行動異常を示す。本研究ではCNの関連分子の遺伝子改変マウスを複数系統入手し、網羅的行動解析を行なった。CNの関連分子として、α-Ca^<2+>/CaM依存性リン酸化酵素II(αCaMKII)、リアノジン受容体3型(RyR3)、神経型NO合成酵素(nNos)、Ca^<2+>/CaM依存性リン酸化酵素IVなどを対象として。RyR3欠損マウスは顕著な活動性の亢進、社会的行動の低下などの行動異常、そして潜在抑制の障害が見られた。nNOS欠損マウスでは活動性の亢進とうつ様行動の低下、作業記憶の低下が見られ、ドーパミンD1受容体のシグナルが活性化していることも明らかとなった。また、CaMKIV欠損マウスは参照記憶の障害や不安様行動の低下を示した。解析したマウスの中で最も顕著な精神疾患様の表現型を示したαCaMKIIヘテロ欠損マウスでは、作業記憶の顕著な障害、著しい攻撃性、活動性の亢進、不安様行動の低下がみられ、さらに活動性には2～3週間程度のゆっくりとした周期的な大きな波が認められた。これらの行動異常のパターンは統合失調症や双極性感情障害等の精神疾患にみられる症状とよく似ていた。さらに、このマウスの海馬の歯状回では、ほとんどの神経細胞は成熟段階まで達していないことを発見し、この現象を「未成熟歯状回」と名付けた。前脳特異的CN欠損マウスをはじめ、他の精神疾患様行動異常を示す複数の系統の遺伝子改変マウスでも「未成熟歯状回」と同様な現象が生じていることを示唆するデータを得ている。CNが統合失調症の有力な感受性遺伝子の一つであることや、「未成熟歯状回」の遺伝子・タンパク発現パターンがヒト精神疾患患者の死後脳のそれと似ていることなども考慮すると、「未成熟歯状回」と同様な現象がヒト統合失調症でも生じている可能性は高いと考えられる。

Research Products

• [Journal Article] Mice with altered myelin proteolipid protein gene expression display cognitive deficits accompanied by abnormal neuron-glia interactions and decreased conduction velocities (2010)
  • Author(s): Tanaka et al.
  • Journal Title: Journal of Neuroscience 26 Pages: 8363-71
  • Peer Reviewed
• [Journal Article] Comprehensive behavioral analysis of calcium/calmodulin-dependent protein kinase IV knockout mice (2010)
  • Author(s): Takao et al.
  • Journal Title: PLoS ONE 5(3)
  • Peer Reviewed
• [Journal Article] SDOP-DB : A comparative standardised-protocol database for mouse phenotypic analyses (2010)
  • Author(s): Tanaka et al.
  • Journal Title: Bioinformatics 15 Pages: 1133-4
  • Peer Reviewed
• [Journal Article] Abnormal behavior in a chromosome- engineered mouse model for human 15q11-13 duplication seen in autism (2009)
  • Author(s): Nakatani J et al.
  • Journal Title: Cell 137 Pages: 1235-46
  • Peer Reviewed
• [Journal Article] Comprehensive behavioral phenotyping of ryanodine receptor type 3(RyR3)knockout mice : decreased social contact duration in two social interaction tests (2009)
  • Author(s): Matsuo N et al.
  • Journal Title: Frontiers in Behavioral Neuroscience 3
  • Peer Reviewed
• [Journal Article] Abnormal social behavior, hyperactivity; impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice (2009)
  • Author(s): Tanda et al.
  • Journal Title: Molecular Brain 2 Pages: 19-19
  • Peer Reviewed
• [Journal Article] Neural activity changes underlying the working memory deficit in alpha-CaMKII heterozygous knockout mice (2009)
  • Author(s): Matsuo et al.
  • Journal Title: Frontiers in Behavioral Neuroscience 3 Pages: 20-20
  • Peer Reviewed
• [Journal Article] Inhibition of calpain increases LIS1 expression and partially rescues hl vivo phenotypes in a mouse model of lissencephaly (2009)
  • Author(s): Yamada et al.
  • Journal Title: Nature Medicine 15(10) Pages: 1202-7
  • Peer Reviewed
• [Journal Article] Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system (2009)
  • Author(s): Ohno et al.
  • Journal Title: Nature Neuroscience 12 Pages: 1506-13
  • Peer Reviewed
• [Journal Article] Abnormalities in brain structure and behavior in GSK-3α mutant mice (2009)
  • Author(s): Kaidanovich-Beilin et al.
  • Journal Title: Molecular Brain 2(1) Pages: 35-35
  • Peer Reviewed
• [Journal Article] Dissection of hippocampal dentate gyros from adult mice (2009)
  • Author(s): Hagihara et al.
  • Journal Title: Journal of Visualized Experiments 33
  • Peer Reviewed
• [Journal Article] Ischemia-induced neurogenesis of neocortical layer 1 progenitor cells (2009)
  • Author(s): Ohira et al.
  • Journal Title: Nature Neuroscience 13(2) Pages: 173-9
  • Peer Reviewed
• [Journal Article] Smaller dendritic spines, weaker synaptic transmission but enhanced spatial learning in mice lacking shankl (2008)
  • Author(s): Hung, AY., Futai, K., Sala, C., Valtschanoff, JG., Ryu, J., Burgoon, M., Kidd, FL., Sung, CC., Miyakawa, T., Bear, MF., Weinberg, RJ., and Sheng. M
  • Journal Title: Journal of Neuroscience 28(7) Pages: 1697-1708
  • Peer Reviewed
• [Journal Article] Increased social interaction in mice deficient of the striatal medium spiny neuron-specific phosphodiesterase 10A2 (2008)
  • Author(s): Sano, H., Nagai, Y., Miyakawa, T., Shigemoto, R., Yokoi, M
  • Journal Title: Journal of Neurochemistry 105 Pages: 546-556
  • Peer Reviewed
• [Journal Article] Increased anxiety-like behavior in neuropsin (kallikrein-related peptidase 8) gene-deficient mice (2008)
  • Author(s): Horii, Y., Yamasaki, N., Miyakawa, T., and Shiosaka, S
  • Journal Title: Behavioral Neuroscience 122(3) Pages: 498-504
  • Peer Reviewed
• [Journal Article] Down-regulation of protocadherin-_, A isoforms in mice changes contextual fear conditioning and spatial working memory (2008)
  • Author(s): Fukuda, E., Hamada, S., Hasegawa, S., Katori, S., Sanbo, M., Miyakawa, T., Yamamoto, T., Yamamoto, H., Hirabayashi, T., Yagi, T
  • Journal Title: European Journal of Neuroscience 28(7) Pages: 1362-76
  • Peer Reviewed
• [Journal Article] Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants (2008)
  • Author(s): Sakae, N., Yamasaki, N. , Kitaichi, K., Fukuda, T, Yamada, M., Yoshikawa, H., Hiranita, T., Tatsumi, Y., Kira, J., Yamamoto, T., Miyakawa, T., Nakayama, KI
  • Journal Title: Human Molecular Genetics 17(20) Pages: 3191-203
  • Peer Reviewed
• [Journal Article] Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia (2008)
  • Author(s): Ikeda, M., Hikita, T., Taya, S., Uraguchi-Asaki, J., Toyo-oka, K., Wynshaw-Boris, A., Ujike, H., Inada, T., Takao, K., Miyakawa, T., Ozaki, N., Kaibuchi, K., Iwata, N
  • Journal Title: Human Molecular Genetics 17(20) Pages: 3212-22
  • Peer Reviewed
• [Journal Article] Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain (2008)
  • Author(s): Imayoshi, I., Sakamoto, M., Ohtsuka, T., Takao, K., Miyakawa, T., Yamaguchi, M., Mori, K., Ikeda, T., Itohara, S., Kageyama, R
  • Journal Title: Nature Neuroscience 11(10) Pages: 1153-61
  • Peer Reviewed
• [Journal Article] Mice lacking the kf-1 gene exhibit increased anxiety but not despair-like behavior (2008)
  • Author(s): Tsujimura, A., Matsuki, M., Takao, K., Yamanishi, K., Miyakawa, T., and Hashimoto-Gotoh, T
  • Journal Title: Frontiers in Behavioral Neuroscience 2 Pages: 4-4
  • Peer Reviewed
• [Journal Article] Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders (2008)
  • Author(s): 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
  • Journal Title: Molecular Brain 1 Pages: 6-6
  • Peer Reviewed
• [Journal Article] Comprehensive behavioral phenotyping of calpastatin-knockout mice (2008)
  • Author(s): Aakajima, R., Takao, K., Huang, SM., Takano, J., Iwata, N., Miyakawa, T., Saido, TC
  • Journal Title: Molecular Brain 1 Pages: 7-7
  • Peer Reviewed
• [Journal Article] Impaired long-term memory retention and working memory in sdymutant mice with a deletion in Dtnbpl, a susceptibility gene for schizophrenia (2008)
  • Author(s): Takao, K., Toyama, K., Nakanishi, K., Hattori, S., Takamura, H., Takeda, M., Miyakawa, T., and Hashimoto, R
  • Journal Title: Molecular Brain 1 Pages: 11-11
  • Peer Reviewed
• [Journal Article] Normal mitochondrial respiratory function is essential for spatial remote memory in mice (2008)
  • Author(s): Tanaka, D., Nakada, K., Takao, K., Ogasawara, E., Kasahara, A., Sato, A., Yonekawa, H., Miyakawa, T., Hayashi, J
  • Journal Title: Molecular Brain 1 Pages: 21-21
  • Peer Reviewed
• [Presentation] Omics analysis of immature dentate gyrus : Possible mechanisms underlying maturation failure of granule cells (2009)
  • Author(s): 宮川剛
  • Organizer: 4^<th> International Conference of Neurons and Brain Disease
  • Place of Presentation: トロント、カナダ
• [Presentation] Deletion of Schnurri-2 causes abnormal behaviors related to psychiatric disorders and failure in the maturation of the dentate granule cells in mice (2009)
  • Author(s): Takao, K., Kobayashi, K., Hagihara, H., Ohira, K., Yamasaki, N., Komada, M., Toyama, K., Takagi, T., Ishii, S., Miyakawa, T.
  • Organizer: 第36回国際生理学会世界大会
  • Place of Presentation: 京都
• [Presentation] 精神疾患の中間表現型としての未成熟歯状回 (2009)
  • Author(s): 宮川剛
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] alpha-CaMKIIヘテロ欠損マウスとShn2欠損マウスの海馬のプロテオミクス解析 (2009)
  • Author(s): 萩原英雄、高雄啓三、遠山桂子、中村政志、高崎昭彦、橋本敬一郎、林宣宏、宮川剛
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] α-CaMKIIヘテロ欠損マウスの海馬遺伝子発現パターン解析 (2009)
  • Author(s): 高雄啓三、宮川剛
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] カルシニューリン抑制因子Zaki-4 Tgマウスの行動解析 (2009)
  • Author(s): 遠山桂子、山崎信幸、高雄啓三、宮川剛
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice (2009)
  • Author(s): Takao, K., Tanda, K., Matsuo, N., Nakanishi, K., Toyama, K., Yamasaki, N., Sugimoto, T., Nishi, A., Miyakawa, T.
  • Organizer: Neuroscience 2009
  • Place of Presentation: シカゴ、アメリカ
• [Presentation] 精神疾患の中間表現型としての未成熟歯状回 (2009)
  • Author(s): 宮川剛
  • Organizer: 第19回日本臨床精神神経薬理学会・第39回日本神経精神薬理学会 合同年会
  • Place of Presentation: 京都
• [Presentation] 精神疾患の中間表現型としての未成熟歯状回 (2009)
  • Author(s): 宮川剛
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜