Modeling of psychiatric disorders using iPSC technologies

• Project/Area Number: 15H04645
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Osaka University
• Principal Investigator: Nakazawa Takanobu 大阪大学, 歯学研究科, 准教授 (00447335)
• Research Collaborator: Hashimoto Hitoshi ; Hashimoto Ryota ; Kuriu Toshihiko
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: iPS細胞 / 統合失調症 / 患者神経細胞 / 分子病態 / 神経細胞分化 / RNA発現解析 / スプライシング反応 / 電気生理学解析 / 電気生理 / トランスレーショナルリサーチ / iPS細胞関連技術 / de novo 変異 / 治療応答性

Outline of Final Research Achievements

Schizophrenia is a common psychiatric disorder that occurs mainly in adolescence, characterized by positive and negative symptoms. Despite a large number of studies, much remains unknown about the molecular etiology of schizophrenia. In this study, we applied iPSC technologies to generate patients' live neuronal cells that enable us to precisely analyze the disease-associated neuronal phenotype. We analyzed the neural function of iPSC-neurons derived from patients from a family with multiple occurrence of schizophrenia and other patients. In these neurons, we found that the impaired gene expression, splicing events and synaptic functions, all of which may be associated with schizophrenia. These results imply that iPSC-derived neurons of patients with schizophrenia provide important insights into the development of new treatment strategies and biomarkers for diagnosis and treatment efficacy.

Academic Significance and Societal Importance of the Research Achievements

統合失調症の病因や病態は不明な点が多く、治療薬の効果も不十分な現状にある。本研究では、直接的に患者由来の神経細胞が解析可能となる患者iPS細胞を介して神経細胞を作製するという、これまでに報告例が少ない新規の系を利用した研究を実施した。その結果、統合失調症と関連することが期待される神経機能の異常（遺伝子発現異常、スプライシング機能異常、及びシナプス機能異常）を同定した。本研究により得られた成果は、疾患の分子病態の同定のみならず、創薬研究、統合失調症の診断や治療に伴う有効性を評価するバイオマーカーの開発、および疾患の細分類系の確立のために極めて有効な基礎データを提供するものである。

Research Products

• [Int'l Joint Research] University of California, Los Angels(米国)
• [Journal Article] mS-11, a mimetic of the mSin3-binding helix in NRSF, ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model. (2019)
  • Author(s): Kawase H, Ago Y, Naito M, Higuchi M, Hara Y, Hasebe S, Tsukada S, Kasai A, Nakazawa T, Mishina T, Kouji H, Takuma K, Hashimoto H.
  • Journal Title: Pharmacol Biochem Behav. Volume: 176 Pages: 1-5
  • DOI: 10.1016/j.pbb.2018.11.003
  • Peer Reviewed / Open Access
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide modulates dendritic spine maturation and morphogenesis via microRNA-132 upregulation. (2019)
  • Author(s): Hayata-Takano A, Kamo T, Kijima H, Seiriki K, Ogata K, Ago Y, Nakazawa T, Shintani Y, Higashino K, Nagayasu K, Shintani N, Kasai A, Waschek JA, Hashimoto H.
  • Journal Title: J Neurosci. Volume: 印刷中 Issue: 22 Pages: 4208-4220
  • DOI: 10.1523/jneurosci.2468-18.2019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Whole-brain block-face serial microscopy tomography at subcellular resolution using FAST. (2019)
  • Author(s): Seiriki K, Kasai A, Nakazawa T, Niu M, Naka Y, Tanuma M, Igarashi H, Yamaura K, Hayata-Takano A, Ago Y, Hashimoto H.
  • Journal Title: Nat Protoc. Volume: 印刷中 Issue: 5 Pages: 1509-1529
  • DOI: 10.1038/s41596-019-0148-4
  • Peer Reviewed / Open Access
• [Journal Article] Unbiased compound screening with a reporter gene assay highlights the role of p13 in the cardiac cellular stress response (2018)
  • Author(s): Inoue N, Hirouchi T, Kasai A, Higashi S, Hiraki N, Tanaka S, Nakazawa T, Nunomura K, Lin B, Omori A, Hayata-Takano A, Kim YJ, Doi T, Baba A, Hashimoto H, Shintani N
  • Journal Title: Biochem Biophys Res Commun. Volume: 495(2) Issue: 2 Pages: 1992-1997
  • DOI: 10.1016/j.bbrc.2017.11.116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Targeted knockdown of the mitochondria-localized protein p13 protects against experimental parkinsonism (2018)
  • Author(s): Inoue N, Ogura S, Kasai A, Nakazawa T, Ikeda K, Higashi S, Isotani A, Baba K, Mochizuki H, Fujimura H, Ago Y, Hayata-Takano A, Seiriki K, Shintani N, Hashimoto H
  • Journal Title: EMBO Reports Volume: 19(3) Issue: 3
  • DOI: 10.15252/embr.201744860
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] β-Arrestin1 and 2 differentially regulate PACAP-induced PAC1 receptor signaling and trafficking. (2018)
  • Author(s): Shintani Y, Hayata-Takano A, Moriguchi K, Nakazawa T, Ago Y, Kasai A, Seiriki K, Shintani N, Hashimoto H.
  • Journal Title: PLoS One Volume: 13 Issue: 5 Pages: e0196946-e0196946
  • DOI: 10.1371/journal.pone.0196946
  • Peer Reviewed / Open Access
• [Journal Article] High-speed and scalable whole-brain imaging in rodents and primates (2017)
  • Author(s): Seiriki K, Kasai A, Hashimoto T, Schulze W, Niu M, Yamaguchi S, Nakazawa T, Inoue K, Uezono S, Takada M, Naka Y, Igarashi H, Tanuma M, Waschek JA, Ago Y, Tanaka KF, Hayata-Takano A, Nagayasu K, Shintani N, Hashimoto R, Kunii Y, Hino M, Matsumoto J, Yabe H, Nagai T, Fujita K, Matsuda T, Takuma K, Baba A, Hashimoto H
  • Journal Title: Neuron Volume: 94 Issue: 6 Pages: 1085-1100
  • DOI: 10.1016/j.neuron.2017.05.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Environmental enrichment attenuates behavioral abnormalities in valproic acid-exposed autism model mice (2017)
  • Author(s): Yamaguchi H, Hara Y, Ago Y, Takano E, Hasebe S, Nakazawa T, Hashimoto H, Matsuda T, Takuma K
  • Journal Title: Behav. Brain Res. Volume: 333 Pages: 67-73
  • DOI: 10.1016/j.bbr.2017.06.035
  • Peer Reviewed / Open Access
• [Journal Article] Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain. (2017)
  • Author(s): Hara Y, Ago Y, Takano E, Hasebe S, Nakazawa T, Hashimoto H, Matsuda T, Takuma K.
  • Journal Title: Molecular Autism Volume: 8 Issue: 1 Pages: 33-33
  • DOI: 10.1186/s13229-017-0149-5
  • Peer Reviewed / Open Access
• [Journal Article] Risperidone and aripiprazole alleviate prenatal valproic acid-induced abnormalities in behaviors and dendritic spine density in mice (2017)
  • Author(s): Hara Y, Ago Y, Taruta A, Hasebe S, Kawase H, Tanabe W, Tsukada S, Nakazawa T, Hashimoto H, Matsuda T, Takuma K
  • Journal Title: Psychopharmacology (Berl) Volume: 234(21) Issue: 21 Pages: 3217-3228
  • DOI: 10.1007/s00213-017-4703-9
  • Peer Reviewed / Open Access
• [Journal Article] Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism (2017)
  • Author(s): Hara Y, Ago Y, Higuchi M, Hasebe S, Nakazawa T, Hashimoto H, Matsuda T, Takuma K
  • Journal Title: Hormones and Behavior Volume: 96 Pages: 130-136
  • DOI: 10.1016/j.yhbeh.2017.09.013
  • Peer Reviewed / Open Access
• [Journal Article] Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine. (2017)
  • Author(s): Nakazawa T, Kikuchi M, Ishikawa M, Yamamori H, Nagayasu K, Matsumoto T, Fujimoto M, Yasuda Y, Fujiwara M, Okada S, Matsumura K, Kasai A, Hayata-Takano A, Shintani N, Numata S, Takuma K, Akamatsu W, Okano H, Nakaya A, Hashimoto H, Hashimoto R.
  • Journal Title: Schizophr Res. Volume: 181 Pages: 75-82
  • DOI: 10.1016/j.schres.2016.10.012
  • NAID: 120007037467
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia. (2017)
  • Author(s): Kinoshita M, Numata S, Tajima A, Yamamori H, Yasuda Y, Fujimoto M, Watanabe S, Umehara H, Shimodera S, Nakazawa T, Kikuchi M, Nakaya A, Hashimoto H, Imoto I, Hashimoto R, Ohmori T.
  • Journal Title: Int J Mol Sci. Volume: 18 Issue: 3 Pages: 632-632
  • DOI: 10.3390/ijms18030632
  • NAID: 120006535029
  • Peer Reviewed / Open Access
• [Journal Article] Double In situ Hybridization for MicroRNAs and mRNAs in Brain Tissues. (2016)
  • Author(s): Kasai A, Kakihara S, Miura H, Okada R, Hayata-Takano A, Hazama K, Niu M, Shintani N, Nakazawa T, Hashimoto H.
  • Journal Title: Front Mol Neurosci. Volume: 9 Pages: 126-126
  • DOI: 10.3389/fnmol.2016.00126
  • Peer Reviewed / Open Access
• [Journal Article] Critical involvement of the orbitofrontal cortex in hyperlocomotion induced by NMDA receptor blockade in mice. (2016)
  • Author(s): Seiriki K, Kasai A, Kuwaki T, Nakazawa T, Yamaguchi S, Hashimoto H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 480 Issue: 4 Pages: 558-563
  • DOI: 10.1016/j.bbrc.2016.10.089
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of Brain-Enriched Guanylate Kinase-Associated Protein (BEGAIN) in Chronic Pain after Peripheral Nerve Injury. (2016)
  • Author(s): Katano T, Fukuda M, Furue H, Yamazaki M, Abe M, Watanabe M, Nishida K, Yao I, Yamada A, Hata Y, Okumura N, Nakazawa T, Yamamoto T, Sakimura K, Takao T, Ito S.
  • Journal Title: eNeuro. Volume: 3 Issue: 5 Pages: 0110-16
  • DOI: 10.1523/eneuro.0110-16.2016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prostaglandin D2 signaling mediated by the CRTH2 receptor is involved in MK-801-induced cognitive dysfunction. (2016)
  • Author(s): Onaka Y, Shintani N, Nakazawa T, Kanoh T, Ago Y, Matsuda T, Hashimoto R, Ohi K, Hirai H, Nagata KY, Nakamura M, Kasai A, Hayata-Takano A, Nagayasu K, Takuma K, Ogawa A, Baba A, Hashimoto H.
  • Journal Title: Behav Brain Res. Volume: 314 Pages: 477-486
  • DOI: 10.1016/j.bbr.2016.07.050
  • Peer Reviewed / Open Access
• [Journal Article] De novo POGZ mutations in sporadic autism disrupt the DNA-binding activity of POGZ. (2016)
  • Author(s): Matsumura K, Nakazawa T, Nagayasu K, Gotoda-Nishimura N, Kasai A, Hayata-Takano A, Shintani N, Yamamori H, Yasuda Y, Hashimoto R, Hashimoto H .
  • Journal Title: Journal of Molecular Psychiatry Volume: 印刷中
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders (2016)
  • Author(s): Nakazawa T, Hashimoto R, Sakoori K, Sugaya Y, Tanimura A, Hashimotodani Y, Ohi K, Yamamori H, Yasuda Y, Umeda-Yano S, Kiyama Y, Konno K, Inoue T, Yokoyama K, Inoue T, Numata S, Ohnuma T, Iwata N, Ozaki N, Hashimoto H, Watanabe M, Manabe T, Yamamoto T, Takeda M, Kano M.
  • Journal Title: Nat Communications Volume: 7 Issue: 1 Pages: 10594-10594
  • DOI: 10.1038/ncomms10594
  • NAID: 120006535052
  • URL: https://pure.teikyo.jp/en/publications/6d10cbbf-3e7f-4e5b-bfce-ab50e6dde489
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder. (2015)
  • Author(s): Hashimoto R, Nakazawa T, Tsurusaki Y, Yasuda Y, Nagayasu K, Matsumura K, Kawashima H, Yamamori H, Fujimoto M, Ohi K, Umeda-Yano S, Fukunaga M, Fujino H, Kasai A, Hayata-Takano A, Shintani N, Takeda M, Matsumoto N, Hashimoto H.
  • Journal Title: Journal of Human Genetics Volume: 61 Issue: 3 Pages: 199-206
  • DOI: 10.1038/jhg.2015.141
  • Peer Reviewed / Open Access
• [Presentation] 妊娠マウスへのバルプロ酸投与は胎仔脳においてmiR-132を増加させる (2019)
  • Author(s): 中澤敬信、原雄大、吾郷由希夫、喜多恵利加、長谷部茂、橋本均、松田敏夫、田熊一敞
  • Organizer: 第92回 日本薬理学会年会
• [Presentation] iPS細胞関連技術を用いた統合失調症の分子病態解析および神経細胞分化の基盤技 術開発 (2018)
  • Author(s): 中澤敬信、橋本亮太、田熊一敞、橋本均
  • Organizer: 日本薬学会 第138回年会
  • Invited
• [Presentation] Involvement of miR-132 in PACAP-dependent morphological changes of dendritic spines. (2018)
  • Author(s): Hayata-Takano A, Kijima H, Kamo T, Shintani Y, Ago Y, Seiriki K, Nakazawa T, Shintani N, Hashimoto H
  • Organizer: CINP World Congress 2018
  • Int'l Joint Research
• [Presentation] Effects of intranasal oxytocin on autism-like behavioral abnormalities in valproic acid-induced mouse model of autism (2018)
  • Author(s): Hara Y, Ago Y, Higuchi M, Hasebe S, Nakazawa T, Hashimoto H, Matsuda M, Takuma K
  • Organizer: World Congress of Basic and Clinical Pharmacology (WCP2018 KYOTO)
  • Int'l Joint Research
• [Presentation] Protein kinase D2 (PRKD2) regulates embryonic neural development (2018)
  • Author(s): Baba M, Matsumura K, Nakazawa T, Nagayasu K, Kasai A, Takuma K, Hashimoto H
  • Organizer: World Congress of Basic and Clinical Pharmacology (WCP2018 KYOTO)
  • Int'l Joint Research
• [Presentation] The de novo Q1042R POGZ mutation in sporadic ASD disrupts the neuronal differentiation (2018)
  • Author(s): Matsumura K, Nakazawa T, Okada S, Nagayasu K, Miura H, Kasai A, Takuma K, Yamamori H, Yasuda Y, Hashimoto R, Hashimoto H
  • Organizer: World Congress of Basic and Clinical Pharmacology (WCP2018 KYOTO)
  • Int'l Joint Research
• [Presentation] 高速・高拡張性全脳イメージングシステムFAST：アンバイアスで仮説フリーに脳内のシンギュラリティを検出する手法へ (2018)
  • Author(s): 橋本均、笠井淳司、勢力薫、中澤敬信
  • Organizer: 第56回 日本生物物理学会年会
  • Invited
• [Presentation] Claustrum is involved in stress-induced anxiety-like behaviors (2018)
  • Author(s): Kasai A, Niu M, Seiriki K, Igarashi H, Tanuma M, Kuwaki T, Nagayasu K, Yamaguchi S, Nakazawa T, Yamanaka A, Hashimoto H
  • Organizer: Cold Spring Harbor Laboratory Meeting (Molecular mechanisms of neuronal connectivity)
  • Int'l Joint Research
• [Presentation] High-speed and high-resolution whole-brain imaging system FAST (block-face-serial-microscopy tomography) (2018)
  • Author(s): Hashimoto H, Seiriki K, Kasai A, Nakazawa T
  • Organizer: Cold Spring Harbor Conference Asia
  • Int'l Joint Research / Invited
• [Presentation] Whole-brain analysis of the NMDA receptor antagonist-induced neuronal activation in mice using hifh-speed and high-resolution imaging system FAST (block-face serial microscopy tomography) (2018)
  • Author(s): Seiriki K, Kasai A, Nakazawa T, Hashimoto H
  • Organizer: Cold Spring Harbor Conference Asia
  • Int'l Joint Research
• [Presentation] iPS細胞関連技術とヒト型疾患モデルマウスを用いた精神疾患の分子病態解析 (2018)
  • Author(s): 中澤敬信、橋本亮太、田熊一敞、橋本均
  • Organizer: 第28回日本臨床精神神経薬理学会 第48回日本神経精神薬理学会 合同年会
  • Invited
• [Presentation] 前頭葉を標的とする自閉症スペクトラム障害の新たな治療戦略の可能性 (2018)
  • Author(s): 田熊一敞、原雄大、吾郷由希夫、橋本均、中澤敬信、松田敏夫
  • Organizer: 第28回日本臨床精神神経薬理学会 第48回日本神経精神薬理学会 合同年会
  • Invited
• [Presentation] 自閉スペクトラム症に高頻度に認めるPOGZ遺伝子座の患者特異的de novo変異の表現型解析 (2017)
  • Author(s): 中澤敬信、田熊一敞、橋本亮太、橋本均
  • Organizer: 第39回日本生物学的精神医学会・第47回日本神経精神薬理学会 合同年会
  • Invited
• [Presentation] Whole-brain mapping analysis of the NMDAR antagonist-induced neuronal activation. (2017)
  • Author(s): Seiriki K, Kasai A, Hashimoto T, Kuwaki T, Niu M, Naka Y, Igarashi H, Nakazawa T, Yamaguchi S, Ago Y, Hashimoto H
  • Organizer: Neuroscience 2017, Annual Meeting of Society for Neuroscience, USA
  • Int'l Joint Research
• [Presentation] High-speed serial-sectioning imaging for whole brain analysis with high scalability. (2017)
  • Author(s): Kasai A, Seiriki S, Hashimoto T, Niu M, Yamaguchi S, Naka Y, Igarashi H, Tanuma M, Nakazawa T, Inoue K-I, Takada M, Fujita K, Hashimoto H
  • Organizer: Neuroscience 2017, Annual Meeting of Society for Neuroscience, USA
  • Invited
• [Presentation] ASD-associated de novo mutations in POGZ impair the DNA-binding activity of POGZ (2016)
  • Author(s): Nakazawa T, Matsumura K, Nagayasu K, Kasai A, Hayata-Takano A, Shintani N, Takuma K, Yamamori H, Yasuda Y, Hashimoto R, Hashimoto H
  • Organizer: 55th Annual Meeting, ACNP
  • Place of Presentation: アメリカ ハリウッド市
  • Year and Date: 2016-12-04
  • Int'l Joint Research
• [Presentation] iPS細胞関連技術を用いた統合失調症患者のクロザピン応答性の個人間の相違の分子機構解析 (2016)
  • Author(s): 中澤敬信、橋本亮太、橋本均
  • Organizer: 第46回 日本神経精神薬理学会年会
  • Place of Presentation: 韓国 ソウル市
  • Year and Date: 2016-07-02
  • Invited
• [Presentation] iPS細胞関連技術を用いたクロザピン応答性の分子基盤解析 (2016)
  • Author(s): 藤原幹也、菊地正隆、永安一樹、中澤敬信、山森英長、笠井淳司、早田敦子、新谷紀人、藤本美智子、
  • Organizer: 第89回 日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-09
• [Presentation] 統合失調症関連遺伝子のマウス脳における発現解析 (2016)
  • Author(s): 岩田晋平、松村憲佑、永安一樹、馬場優志、笠井淳司、早田敦子、新谷紀人、田熊一敞、中澤敬信、 橋本均
  • Organizer: 第130回日本薬理学会近畿部会
  • Place of Presentation: 京都府 京都市 京都大学講堂
• [Presentation] 自閉症の疾患特異的候補遺伝子の機能的スクリーニング (2015)
  • Author(s): 松村憲佑、橋本亮太、中澤敬信、鶴崎美徳、安田由華、永安一樹、川島和、山森英長、藤本美智子、
  • Organizer: 第38回日本神経科学会大会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-07-28
• [Remarks] 大阪大学大学院歯学研究科薬理学教室
  • URL: https://web.dent.osaka-u.ac.jp/pharm/
• [Remarks] 大阪大学大学院薬学研究科神経薬理学分野
  • URL: http://molpharm.umin.jp/
• [Remarks] 大阪大学大学院薬学研究科神経薬理学分野
  • URL: http://molpharm.umin.jp/index.html
• [Remarks] 大阪大学大学院歯学研究科薬理学教室
  • URL: http://web.dent.osaka-u.ac.jp/~pharm/