Modelling psychiatric disorders with iPS technology and genetically engineered mice

• Project/Area Number: 18H02574
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Tokyo University of Agriculture (2020); Osaka University (2018-2019)
• Principal Investigator: Nakazawa Takanobu 東京農業大学, 生命科学部, 教授 (00447335)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: iPS細胞 / トランスレーショナル研究 / 統合失調症 / 自閉スペクトラム症 / ゲノムコピー数変異 / de novo突然変異 / 精神疾患 / 自閉症

Outline of Final Research Achievements

In mice models of psychiatric disorders with POGZ Q1042R mutation or 3q29 deletion, both of which are expected to be strongly associated with psychiatric disorders, we found psychiatric disorder-related behavioral abnormalities, including impaired prepulse inhibition, impaired social behavior, repetitive and persistent behaviors and abnormal ultrasonic vocalization. We also found the neural activity in the anterior cingulate cortex in the POGZ mutant mice and the auditory cortex in the mice with 3q29 deletion were abnormally activated. Importantly, we found that the social behavioral abnormalities in the POGZ mutant mice and mice with 3q29 deletion can be recovered pharmacologically even in the adult stages. These results are useful not only for clarifying the molecular pathogenesis of the disease, but also for providing fundamental biological information for drug discovery research.

Academic Significance and Societal Importance of the Research Achievements

精神疾患分野では、患者に共通した疾患関連遺伝子を同定することができておらず、発症や病態の分子機序がいまだ不明である。従って、患者に共通する変異のみならず、病態に直結することが期待される効果サイズが大きい変異を持つ患者を地道に解析することが重要である。POGZ変異や3q29領域欠失は、その頻度は稀であるものの、疾患との関連性が強く示唆されており、本研究で得られた成果は、精神疾患の分子病態の解明に貢献するのみならず、創薬研究ための基礎データを提供するものである。

Research Products

• [Journal Article] Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder (2021)
  • Author(s): Kitagawa Kohei、Matsumura Kensuke、Baba Masayuki、Kondo Momoka、Takemoto Tomoya、Nagayasu Kazuki、Ago Yukio、Seiriki Kaoru、Hayata-Takano Atsuko、Kasai Atsushi、Takuma Kazuhiro、Hashimoto Ryota、Hashimoto Hitoshi、Nakazawa Takanobu
  • Journal Title: Molecular Brain Volume: 14 Issue: 1 Pages: 56-56
  • DOI: 10.1186/s13041-021-00769-8
  • Peer Reviewed / Open Access
• [Journal Article] Lipocalin-type prostaglandin D synthase regulates light-induced phase advance of the central circadian rhythm in mice (2020)
  • Author(s): Kawaguchi, C., Shintani, N., Hayata-Takano, A., Hatanaka, M., Kuromi, A., Nakamura, R., Yamano, Y., Shintani, Y., Nagai, K., Tsuchiya, S., Sugimoto, Y., Ichikawa, A., Okuno, Y., Urade, Y., Hirai, H., Nagata, K., Nakamura, M., Narumiya, S., Nakazawa, T., Kasai, A., Ago, Y., Takuma, K., Baba, A., and Hashimoto, H.
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 557-557
  • DOI: 10.1038/s42003-020-01281-w
  • Peer Reviewed / Open Access
• [Journal Article] Activation of the VPAC2 Receptor Impairs Axon Outgrowth and Decreases Dendritic Arborization in Mouse Cortical Neurons by a PKA-Dependent Mechanism (2020)
  • Author(s): Takeuchi Shuto、Kawanai Takuya、Yamauchi Ryosuke、Chen Lu、Miyaoka Tatsunori、Yamada Mei、Asano Satoshi、Hayata-Takano Atsuko、Nakazawa Takanobu、Yano Koji、Horiguchi Naotaka、Nakagawa Shinsaku、Takuma Kazuhiro、Waschek James A.、Hashimoto Hitoshi、Ago Yukio
  • Journal Title: Frontiers in Neuroscience Volume: 14 Pages: 521-532
  • DOI: 10.3389/fnins.2020.00521
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes. (2020)
  • Author(s): Matsumura K, (33名中略）, Hashimoto R, (37名中35番目）,Hashimoto H, Nakazawa T.
  • Journal Title: Nat. Commun Volume: 11(1) Issue: 1 Pages: 859-859
  • DOI: 10.1038/s41467-020-14697-z
  • Peer Reviewed / Open Access
• [Journal Article] Autism-associated protein kinase D2 regulates embryonic cortical neuron development. (2019)
  • Author(s): Matsumura K, Baba M, Nagayasu K, Yamamoto K, Kondo M, Kitagawa K, Takemoto T, Seiriki K, Kasai A, Ago Y, Hayata-Takano A, Shintani N, Kuriu T, Iguchi T, Sato M, Takuma K, Hashimoto R, Hashimoto H.
  • Journal Title: Biochem Biophys Res Commun Volume: 519(3) Issue: 3 Pages: 626-632
  • DOI: 10.1016/j.bbrc.2019.09.048
  • Peer Reviewed / Open Access
• [Journal Article] Current Perspective: Modeling of psychiatric disorders using induced pluripotent stem cell-related technologies. (2019)
  • Author(s): Nakazawa T, Hashimoto R, Takuma K, Hashimoto H.
  • Journal Title: J Pharmacol Sci, Volume: 140(4) Issue: 4 Pages: 321-324
  • DOI: 10.1016/j.jphs.2019.06.002
  • Peer Reviewed / Open Access
• [Journal Article] Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome. (2019)
  • Author(s): Baba M, Yokoyama K, Seiriki K, Naka Y, Matsumura K, Kondo M, Yamamoto K, Hayashida M, Kasai A, Ago Y, Nagayasu K, Hayata-Takano A, Takahashi A, Yamaguchi S, Mori D, Ozaki N, Yamamoto T, Takuma K, Hashimoto R, Hashimoto H, Nakazawa T.
  • Journal Title: Neuropsychopharmacology Volume: 44(12) Issue: 12 Pages: 2125-2135
  • DOI: 10.1038/s41386-019-0441-5
  • NAID: 130007811380
  • Peer Reviewed / Open Access
• [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] 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] 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] 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
• [Presentation] オキシトシンの鼻腔内投与はPOGZ-Q1038R点変異マウスの社会性行動異常を改善する (2021)
  • Author(s): 北川 航平，松村 憲佑，馬場 優志，近藤 百香，竹本 智哉，永安 一樹，吾郷 由希夫，笠井 淳司，田熊 一敞，橋本 均，中澤 敬信
  • Organizer: 第94回 日本薬理学会年会
• [Presentation] ヒトiPS細胞技術を用いた精神疾患および発達障害モデルの開発 (2021)
  • Author(s): 中澤敬信
  • Organizer: 第94回 日本薬理学会年会
  • Invited
• [Presentation] 3q29領域欠失変異を有する精神疾患患者のiPS神経細胞の機能解析 (2020)
  • Author(s): 近藤百香、栗生俊彦、馬場優志、北川航平、竹本智哉、永安一樹、山森英長、安田由華、藤本美智子、田熊一敞、小野富三人、橋本亮太、橋本均、中澤敬信
  • Organizer: 第138回日本薬理学会近畿部会
• [Presentation] ヒト染色体3q29欠失モデルマウスを用いた精神疾患の分子病態研究 (2020)
  • Author(s): 馬場優志、勢力薫、近藤百香、北川航平、竹本智哉、笠井淳司、吾郷由希夫、永安一樹、森大輔、尾崎紀夫、山本雅、田熊一敞、橋本亮太、橋本均、中澤敬信
  • Organizer: 第138回日本薬理学会近畿部会
• [Presentation] 疾患iPS細胞を用いた精神疾患の分子病態研究 (2020)
  • Author(s): 中澤敬信
  • Organizer: NPBPPP2020 合同大会
  • Invited
• [Presentation] 脳内シンギュラリティ細胞の探索を目指した全脳イメージングとアンバイアス解析 (2019)
  • Author(s): 橋本均、中澤敬信
  • Organizer: 第19回日本蛋白質科学会年会・第71回日本細胞生物学会大会 合同年次大会
  • Invited
• [Presentation] 自閉スペクトラム症関連遺伝子POGZの患者特異的de novo変異の大脳皮質神経分化における表現型解析 (2019)
  • Author(s): 松村憲佑、勢力薫、永瀬将志、綾部信哉、山田郁子、古瀬民生、山本果奈、北川航平、猪口徳一、佐藤真、山口瞬、田村勝、若菜茂晴、吉木淳、渡部文子、岡野栄之、田熊一敞、橋本亮太、橋本均、中澤敬信
  • Organizer: 第42回日本神経科学大会・第62回日本神経化学会大会（NEURO2019）
• [Presentation] 多発家系患者のiPS分化神経細胞を用いた統合失調症の分子病態解析 (2019)
  • Author(s): 山本果奈、栗生俊彦、中澤敬信、松村憲佑、永安一樹、馬場優志、山森英長、安田由華、藤本美智子、鶴崎美徳、松本直通、田熊一敞、橋本亮太、橋本均
  • Organizer: 第42回日本神経科学大会・第62回日本神経化学会大会（NEURO2019）
• [Presentation] 全脳イメージングシステムFASTを用いたアンバイアスで仮説に依らない脳内シンギュラリティの検出 (2019)
  • Author(s): 橋本均、中澤敬信、勢力薫、笠井淳司
  • Organizer: 第57回日本生物物理学会年会
  • Invited
• [Presentation] ヒトiPS細胞技術を用いた精神疾患モデルの開発 (2019)
  • Author(s): 中澤敬信、橋本亮太、田熊一敞、橋本均
  • Organizer: 第93回日本薬理学会年会
  • Invited
• [Presentation] iPS細胞を用いた精神疾患のメカニズム研究と創薬への応用 (2019)
  • Author(s): 中澤敬信、橋本亮太、田熊一敞、橋本均
  • Organizer: 第93回日本薬理学会年会
  • Invited
• [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] 多発家系患者のiPS分化神経細胞を用いた統合失調症の分子病態解析 (2018)
  • Author(s): 山本果奈、松村憲佑、中澤敬信、永安一樹、栗生俊彦、馬場優志、田熊一敞、鶴崎美徳、安田由華、山森英長、松本直通、橋本亮太、橋本均
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2018
• [Presentation] 複数の自閉症スペクトラム障害患者にde novo変異が認められるPRKD2は神経発達に関与する (2018)
  • Author(s): 馬場優志、松村憲佑、中澤敬信、永安一樹、笠井淳司、田熊一敞、橋本均
  • Organizer: 第61回 日本神経化学会大会・第40回日本生物学的精神医学会
• [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