非定型炎症を伴う精神疾患モデル動物を活用したマイクロ精神病態の同定と分子機序解明

2014 Fiscal Year Annual Research Report

• Project Area: Unraveling micro-endophenotypes of psychiatric disorders at the molecular, cellular and circuit levels.
• Project/Area Number: 25116526
• Research Institution: Fujita Health University
• Principal Investigator: 宮川 剛 藤田保健衛生大学, 総合医科学研究所, 教授 (10301780)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 脳・神経 / 脳神経疾患 / 細胞・組織 / シグナル伝達

Outline of Annual Research Achievements

各種精神疾患モデルマウスの系統のうちヒト遺伝学的解析や死後脳解析での知見を考慮の上、最も妥当性の高いと考えられるSchnurri-2 KOマウスに特に注目し引き続き以下の解析を進めた。
(1) 遺伝的・環境的要因が脳の軽度慢性炎症を引き起こすメカニズムの解明：ジーンチップデータに基づいたバイオインフォマティクス解析により、炎症・神経過活動・「未成熟歯状回」の遺伝子発現パターンが非常に似ていることがわかってきた。環境的要因が脳の軽度慢性炎症を引き起こすメカニズムを調べるためストレス負荷モデルおよび神経過活動モデルマウスにおいて脳内分子発現変化の予備的解析を行った。今後匹数を増やして詳細な検討を行う。
(2) 脳の軽度慢性炎症が原因となって生じるマイクロエンドフェノタイプの同定：Schnurri-2 KOマウスを用いた3D電顕（電子顕微鏡）によるコネクトーム解析により、スパインレベルでの変化がわかりつつある。また、統合失調症患者とそのモデルマウスでは、DNAメチル化などのエピゲノム異常が生じている可能性が示唆されている。慢性炎症を呈するモデルマウスの脳においてどのようなエピジェネティクス変化が生じているか調べるためメチローム解析を行い、現在データの解析中である。さらに海馬のジーンチップデータのバイオインフォマティクス解析により炎症を始めとした各種の分子レベルでの表現型を正常化する可能性が考えられる薬剤を複数選定し、実際にマウスに投与した。現段階では行動レベルでのスクリーニングで顕著な効果はまだ得られていないが、今後さらに別の薬剤や複数の薬剤の併用などの検討を行う。
また、当初の計画以上の進展としてジーンチップデータのインフォマティクス解析により統合失調症患者の前頭皮質が擬似的未成熟状態にある可能性があることが分かった。新たなマイクロエンドフェノタイプ同定への一助になると考えられる。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Comprehensive behavioral study of mGluR3 knockout mice: implication in schizophrenia related endophenotypes. (2014)
  • Author(s): Fujioka R, Nii T, Iwaki A, Shibata A, Ito I, Kitaichi K, Nomura M, Hattori S, Takao K, Miyakawa T, Fukumaki Y.
  • Journal Title: Mol Brain Volume: 7 Pages: 31
  • DOI: 10.1186/1756-6606-7-31
  • Peer Reviewed / Open Access
• [Journal Article] Hippocampal neurogenesis regulates forgetting during adulthood and infancy. (2014)
  • Author(s): Akers KG, Martinez-Canabal A, Restivo L, Yiu AP, De Cristofaro A, Hsiang HL, Wheeler AL, Guskjolen A, Niibori Y, Shoji H, Ohira K, Richards BA, Miyakawa T, Josselyn SA, Frankland PW.
  • Journal Title: Science Volume: 344(6184) Pages: 598-602
  • DOI: 10.1126/science.1248903
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptomic evidence for immaturity of the prefrontal cortex in patients with schizophrenia. (2014)
  • Author(s): Hagihara H, Ohira K, Takao K, Miyakawa T.
  • Journal Title: Mol Brain Volume: 7 Pages: 41
  • DOI: 10.1186/1756-6606-7-41
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Enhanced stability of hippocampal place representation caused by reduced magnesium block of NMDA receptors in the dentate gyrus. (2014)
  • Author(s): Hayashi Y, Nabeshima Y, Kobayashi K, Miyakawa T, Tanda K, Takao K, Suzuki H, Esumi E, Noguchi S, Matsuda Y, Sasaoka T, Noda T, Miyazaki JI, Mishina M, Funabiki K, Nabeshima YI.
  • Journal Title: Mol Brain Volume: 7 Pages: 44
  • DOI: 10.1186/1756-6606-7-44
  • Peer Reviewed / Open Access
• [Journal Article] Mechanisms for interferon-α-induced depression and neural stem cell dysfunction. (2014)
  • Author(s): Zheng LS, Hitoshi S, Kaneko N, Takao K, Miyakawa T, Tanaka Y, Xia H, Kalinke U, Kudo K, Kanba S, Ikenaka K, Sawamoto K.
  • Journal Title: Stem cell Reports Volume: 3(1) Pages: 73-84
  • DOI: 10.1016/j.stemcr.2014.05.015
  • Peer Reviewed / Open Access
• [Journal Article] Genomic responses in mouse models greatly mimic human inflammatory diseases. (2014)
  • Author(s): Takao K, Miyakawa T
  • Journal Title: Proc Natl Acad Sci USA Volume: 112(4) Pages: 1167-72
  • DOI: 10.1073/pnas.1401965111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system. (2014)
  • Author(s): Watanabe S, Ageta-Ishihara N, Nagatsu S, Takao K, Komine O, Endo F, Miyakawa T, Misawa H, Takahashi R, Kinoshita M, Yamanaka K.
  • Journal Title: Mol Brain Volume: 7 Pages: 62
  • DOI: 10.1186/s13041-014-0062-1
  • Peer Reviewed / Open Access
• [Journal Article] IL1RAPL1 knockout mice show spine density decrease, learning deficiency, hyperactivity and reduced anxiety-like behaviours. (2014)
  • Author(s): Yasumura M, Yoshida T, Yamazaki M, Abe M, Natsume R, Kanno K, Uemura T, Takao K, Sakimura K, Kikusui T, Miyakawa T, Mishina M.
  • Journal Title: Sci Rep. Volume: 4 Pages: 6613
  • DOI: 10.1038/srep06613
  • Peer Reviewed / Open Access
• [Presentation] 精神疾患の中間表現型としての未成熟脳 (2015)
  • Author(s): 宮川剛
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] Transcriptomic effects of antidepressant treatment and glucocorticoid receptor-overexpression on the maturational status of brain cells in mice (2014)
  • Author(s): Tsuyoshi Miyakawa
  • Organizer: ACNP 53rd Annual Meeting
  • Place of Presentation: Arizona, USA
  • Year and Date: 2014-12-07 – 2014-12-11
• [Presentation] ranscriptomic evidence for immaturity of the prefrontal cortex in patients with schizophrenia (2014)
  • Author(s): Hideo Hagihara, Koji Ohira, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: Neuroscience 2014
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Contrasting expression patterns for immaturity and maturity marker genes in the dentate gyrus between mouse line with ‘immature dentate gyrus’ and mice overexpressing glucocorticoid receptor (2014)
  • Author(s): Hisatsugu Koshimizu, Hideo Hagihara, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: Neuroscience 2014
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Cohort removal induces hyperthermia, increased pain sensitivity, and decreased anxiety-like behavior (2014)
  • Author(s): Keizo Takao, Satoko Hattori, Hirotaka Shoji, Tsuyoshi Miyakawa
  • Organizer: Neuroscience 2014
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Transcriptomic evidence for immaturity in the frontal cortex and dentate gyrus of mice treated with antidepressants (2014)
  • Author(s): Koji Ohira, Hideo Hagihara, Rika Takeuchi, Tsuyoshi Miyakawa
  • Organizer: Neuroscience 2014
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Transcriptomic evidence for immaturity of the prefrontal cortex in patients with schizophrenia (2014)
  • Author(s): Hideo Hagihara, Koji Ohira, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: Molecular and Cellular Cognition Society
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-14
• [Presentation] Contrasting expression patterns for immaturity and maturity marker genes in the dentate gyrus between mouse line with ‘immature dentate gyrus’ and mice overexpressing glucocorticoid receptor (2014)
  • Author(s): Hisatsugu Koshimizu, Hideo Hagihara, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: Molecular and Cellular Cognition Society
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-14
• [Presentation] 遺伝子改変マウスの行動解析を起点とする精神疾患の研究―マウスはモデルになりますー (2014)
  • Author(s): 宮川剛
  • Organizer: 第36回日本生物学的精神医学会・第57回日本神経化学会大会
  • Place of Presentation: 奈良県文化会館、奈良県新公会堂
  • Year and Date: 2014-09-29 – 2014-10-01
• [Presentation] 統合失調症の脳内中間表現型としての軽度慢性炎症―マウスモデルを用いた研究― (2014)
  • Author(s): 宮川剛
  • Organizer: 第36回日本生物学的精神医学会・第57回日本神経化学会大会
  • Place of Presentation: 奈良県文化会館、奈良県新公会堂
  • Year and Date: 2014-09-29 – 2014-10-01
• [Presentation] Bidirectional change of maturation status of cells in the brain: Relevance to neuropsychiatric disorder (2014)
  • Author(s): Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Genomic responses in mouse models greatly mimic human inflammatory diseases: In defense of mouse models for studying human disorders (2014)
  • Author(s): Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Comprehensive behavioral analysis of forebrain and dentate gyrus-specific Schnurri-2 knockout mice (2014)
  • Author(s): Satoko Hattori, Keizo Takao, Maya Yamazaki, Keiko Toyama, Juzoh Umemori, Kenji Sakimura, Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Transcriptomic evidence for immaturity of the prefrontal cortex in patients with schizophrenia (2014)
  • Author(s): Hideo Hagihara, Koji Ohira, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Transcriptomic evidence for the immaturity in the frontal cortex of mice treated with antidepressants (2014)
  • Author(s): Koji Ohira, Hideo Hagihara, Rika Takeuchi, Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Contrasting expression pattern for immaturity and maturity marker genes in the dentate gyrus between mouse lines with “immature dentate gyrus” and mice overexpressing glucocorticoid receptor (2014)
  • Author(s): Hisatsugu Koshimizu, Hideo Hagihara, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Remote memory deficit in three strains of mutant mice immature dentate gyrus phenotype (2014)
  • Author(s): Hirotaka Shoji, Tsuyoshi Miyakawa, Shunsuke Ishii, Isabella A Graef, Gerald R Crabtree, Paul W Frankland, Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Bidirectional change of maturation status of cells in the brain: relevant to neuropsychiatric disorders (2014)
  • Author(s): Tsuyoshi Miyakawa
  • Organizer: 9th International Conference for Neurons and Brain Disease
  • Place of Presentation: スペイン、マドリード
  • Year and Date: 2014-07-11 – 2014-07-16
• [Presentation] 精神疾患の中間表現型としての未成熟脳 (2014)
  • Author(s): 宮川剛
  • Organizer: 第110回日本精神神経学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-06-26 – 2014-06-28
• [Presentation] Transcriptomic evidence for immaturity of the prefrontal cortex in patients with schizophrenia (2014)
  • Author(s): Hideo Hagihara, Koji Ohira, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: 29th CINP World Congress of Neuropsychopharmacology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-22 – 2014-06-26
• [Presentation] Retrospective prediction of behavioral state by hippocampal transcriptomes (2014)
  • Author(s): Hideo Hagihara, Tomoyasu Horikawa, Hironori K. Nakamura, Hirotaka Shoji, Yukiyasu Kamitani, Tsuyoshi Miyakawa
  • Organizer: 29th CINP World Congress of Neuropsychopharmacology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-22 – 2014-06-26