Genomic analysis-based neuropharmacological study on basal ganglia-thalamocortical circuits for new drug discovery in schizophrenia

• Project/Area Number: 20H03428
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Nagoya University
• Principal Investigator: Yamada Kiyofumi 名古屋大学, 医学部附属病院, 教授 (30303639)
• Co-Investigator(Kenkyū-buntansha): 永井 拓 藤田医科大学, 精神・神経病態解明センター, 教授 (10377426) ; 溝口 博之 名古屋大学, 医学部附属病院, 准教授 (70402568)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2020: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 統合失調症 / Rhoキナーゼ / 抗精神病作用 / Fasudil / ROCK2阻害薬 / Ｒhoキナーゼ / 動物モデル / 抗精神病薬

Outline of Research at the Start

統合失調症 (SCZ)はアンメット・メディカルニーズの高い疾患であり、従来の抗精神病薬の延長線上ではない新しい作用機序を有する治療薬の開発は喫緊の課題である。これまでに我々は、SCZの新規治療標的としてRhoキナーゼを同定し、Rhoキナーゼ阻害薬の抗精神病作用を確認して国際特許を申請した。本研究では、高次脳機能制御におけるRhoキナーゼの役割を解明し、そのメカニズムを明らかにする。

Outline of Final Research Achievements

We have generated a disease model mouse with ARHGAP10 gene mutation identified in a Japanese schizophrenia (SCZ) patient and identified Rho kinase as a novel therapeutic target by phenotypic analysis. In order to elucidate the role of Rho kinase in the regulation of higher brain functions, we performed pharmacologic functional analysis with fasudil, a non-selective ROCK inhibitor, and KD025, a selective ROCK2 inhibitor in this study. We also analyzed the effects of ROCK inhibitors on neuronal activity in striatal dopamine D1 receptor-expressing medium spiny neurons (DIR-MSN) in which GCaMP has been expressed with AAV expression vector. Furthermore, the effects of Fasudil and KD025 on depolarization-evoked dopamine (DA) and serotonin (5HT) release in the nucleus accumbens were analyzed using an in vivo dialysis system. Our findings suggest that ROCK2 could be a better drug target for developing novel antipsychotics.

Academic Significance and Societal Importance of the Research Achievements

SCZは思春期以降に発症する代表的な精神疾患である。有病率は約1%であり、本邦の患者数は79.5万人、その内18.7万人は入院治療を受けており、経済的損失は、間接的費用を含めると年間2.8兆円に達する。SCZの病因・病態は未解明であり、その治療は抗精神病薬を用いた対症療法が中心であるが、十分な薬物治療をしても約2/3の患者には精神障害が残存し、再発・再燃を繰り返す。したがって、従来の抗精神病薬の延長線上ではない、真に有効な治療薬の開発は患者・家族だけでなく社会的要請である。本研究成果は、新規抗精神病薬の開発のための創薬標的としてROCK2を同定した。

Research Products

• [Journal Article] Inhibition of Rho-kinase ameliorates decreased spine density in the medial prefrontal cortex and methamphetamine-induced cognitive dysfunction in mice carrying schizophrenia-associated mutations of the Arhgap10 gene. (2023)
  • Author(s): Tanaka R, Liao J, Hada K, Mori D, Nagai T, Matsuzaki T, Nabeshima T, Kaibuchi K, Ozaki N, Mizoguchi H, Yamada K.
  • Journal Title: Pharmacological Research Volume: 187 Pages: 106589-106589
  • DOI: 10.1016/j.phrs.2022.106589
  • Peer Reviewed / Open Access
• [Journal Article] Antipsychotic-like effects of fasudil, a Rho-kinase inhibitor, in a pharmacologic animal model of schizophrenia. (2022)
  • Author(s): Takase S, Liao J, Liu Y, Tanaka R, Miyagawa Y, Sawahata M, Sobue A, Mizoguchi H, Nagai T, Kaibuchi K, Ozaki N, Yamada K.
  • Journal Title: European Journal of Pharmacology Volume: 15;931 Pages: 175207-175207
  • DOI: 10.1016/j.ejphar.2022.175207
  • Peer Reviewed / Open Access
• [Journal Article] Mice with exonic RELN deletion identified from a patient with schizophrenia have impaired visual discrimination learning and reversal learning in touchscreen operant tasks (2022)
  • Author(s): Liao Jingzhu、Dong Geyao、Wulaer Bolati、Sawahata Masahito、Mizoguchi Hiroyuki、Mori Daisuke、Ozaki Norio、Nabeshima Toshitaka、Nagai Taku、Yamada Kiyofumi
  • Journal Title: Behavioural Brain Research Volume: 416 Pages: 113569-113569
  • DOI: 10.1016/j.bbr.2021.113569
  • NAID: 120007190677
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] New Strategies for the Treatment of Neuropsychiatric Disorders Based on Reelin Dysfunction (2022)
  • Author(s): Tsuneura Yumi、Nakai Tsuyoshi、Mizoguchi Hiroyuki、Yamada Kiyofumi
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 3 Pages: 1829-1829
  • DOI: 10.3390/ijms23031829
  • Peer Reviewed / Open Access
• [Journal Article] Microinjection of Reelin into the mPFC prevents MK-801-induced recognition memory impairment in mice (2021)
  • Author(s): Sawahata Masahito、Asano Hiroki、Nagai Taku、Ito Norimichi、Kohno Takao、Nabeshima Toshitaka、Hattori Mitsuharu、Yamada Kiyofumi
  • Journal Title: Pharmacological Research Volume: 173 Pages: 105832-105832
  • DOI: 10.1016/j.phrs.2021.105832
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mice carrying a schizophrenia-associated mutation of the Arhgap10 gene are vulnerable to the effects of methamphetamine treatment on cognitive function: association with morphological abnormalities in striatal neurons (2021)
  • Author(s): Hada K, Wulaer B, Nagai T, Itoh N, Sawahata M, Sobue A, Mizoguchi H, Mori D, Kushima I, Nabeshima T, Ozaki N, Yamada K.
  • Journal Title: Mol Brain Volume: 14(1) Issue: 1 Pages: 21-21
  • DOI: 10.1186/s13041-021-00735-4
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of Reelin signaling and neurodevelopmental trajectory in primary cultured cortical neurons with RELN deletion identified in schizophrenia (2021)
  • Author(s): Tsuneura Yumi、Sawahata Masahito、Itoh Norimichi、Miyajima Ryoya、Mori Daisuke、Kohno Takao、Hattori Mitsuharu、Sobue Akira、Nagai Taku、Mizoguchi Hiroyuki、Nabeshima Toshitaka、Ozaki Norio、Yamada Kiyofumi
  • Journal Title: Neurochemistry International Volume: 144 Pages: 104954-104954
  • DOI: 10.1016/j.neuint.2020.104954
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reelin Supplementation Into the Hippocampus Rescues Abnormal Behavior in a Mouse Model of Neurodevelopmental Disorders (2020)
  • Author(s): Ibi Daisuke、Nakasai Genki、Koide Nayu、Sawahata Masahito、Kohno Takao、Takaba Rika、Nagai Taku、Hattori Mitsuharu、Nabeshima Toshitaka、Yamada Kiyofumi、Hiramatsu Masayuki
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 14 Pages: 285-285
  • DOI: 10.3389/fncel.2020.00285
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of astroglial major histocompatibility complex class I in the medial prefrontal cortex impairs visual discrimination learning in mice (2020)
  • Author(s): Wulaer Bolati、Hada Kazuhiro、Sobue Akira、Itoh Norimichi、Nabeshima Toshitaka、Nagai Taku、Yamada Kiyofumi
  • Journal Title: Molecular Brain Volume: 13 Issue: 1 Pages: 170-170
  • DOI: 10.1186/s13041-020-00710-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Spine morphological changes in Reln-del mice（リーリンモデルマウスにスパインの形態変化について研究） (2022)
  • Author(s): Youyun Zhu、Yumi Tsuneura、Hiroyuki Mizoguchi、Masahito Sawahata、Daisuke Mori、Takao Kohno、Mitsuharu Hattori、Toshitaka Nabeshima、Norio Ozaki、Kiyofumi Yamada.
  • Organizer: NEURO2022
• [Presentation] Phosphorylated twinfilin1 plays a major role in dendritic spine development, but not brain layer formation (2022)
  • Author(s): Geyao Dong, Norimichi Itoh, Tetsuo Matsuzaki, Hiroyuki Mizoguchi, Daisuke Mori, Taku Nagai,Toshitaka Nabeshima, Norio Ozaki, Kiyofumi Yamada
  • Organizer: BPCNPNPPP4学会合同年会
• [Presentation] Neuronal morphological impairments in the model mice carrying the same deletion of RELN gene that was identified in a Japanese schizophrenia patient. (2022)
  • Author(s): 朱 悠韻、常浦 祐未、溝口 博之、澤幡 雅仁、森 大輔、河野 孝夫、服部 光治、鍋島 俊隆、尾崎 紀夫、山田 清文
  • Organizer: 第142回日本薬理学会近畿部会
• [Presentation] Phosphorylation of twinfilin-1 involved in the reelin signaling plays a crucial role in spine development (2022)
  • Author(s): Geyao Dong, Norimichi Itoh, Hiroyuki Mizoguchi , Tetsuo Matsuzaki, Daisuke Mori, Taku Nagai, Toshitaka Nabeshima, Norio Ozaki, Kiyofumi Yamada
  • Organizer: JPW2022
• [Presentation] Arhgap10遺伝子変異マウスの神経活動の解析にむけたin vivoカルシウムイメージング法の確立 (2022)
  • Author(s): 田中里奈子、羽田和弘、溝口博之、澤幡雅仁、永井拓、森大輔、鍋島俊隆、貝淵弘三、尾崎紀夫、山田清文
  • Organizer: 第95回日本薬理学会年会
• [Presentation] The Mice Carrying Schizopherenia-associated Mutation of Arhgap10 Gene are Vulnerable to Psychostimulants:Association with Morphological Abnormalities in Striatal Neurons. (2021)
  • Author(s): Kiyofumi Yamada, Kazuhiro Hada, Taku Nagai
  • Organizer: CINP2021 VIRTUAL WORLD CONGRESS
  • Int'l Joint Research
• [Presentation] Development of ADAMTS-3 Knockdown Method for Enhancement of Reelin Signaling in vitro. (2021)
  • Author(s): Yumi Tsuneura, Masahito Sawahata, Norimichi Ito, Takao Kohno, Mitsuharu Hattori, Taku Nagai, Kiyofumi Yamada.
  • Organizer: CINP2021 VIRTUAL WORLD CONGRESS
  • Int'l Joint Research
• [Presentation] Comprehensive Phosphoproteomic Analysis in Reelin Mutant Mice Revealed a Crucial Role of Twinfilin-1 in Spine Development. (2021)
  • Author(s): Norimichi Ito, Takaaki Matsui, Ayato sato, Kazuhiro Hada, Yumi Tsuneura, Taku Nagai, Toshitaka Nabeshima, Kiyofumi Yamada
  • Organizer: CINP2021 VIRTUAL WORLD CONGRESS
  • Int'l Joint Research
• [Presentation] The Mice Carrying Schizopherenia-associated Mutation of Arhgap10 Gene are Vulnerable to Psychostimulants: Association with Morphological Abnormalities in Striatal Neurons. (2021)
  • Author(s): Kiyofumi Yamada, Kazuhiro Hada, Taku Nagai
  • Organizer: CINP2021 VIRTUAL WORLD CONGRESS
  • Int'l Joint Research
• [Presentation] Comprehensive Phosphoprotemic Analysis in Reelin Mutant Mice Revealed a Crucial Rolr of Twinfilin-1 in Spine Development. (2021)
  • Author(s): Norimichi Ito、Takaaki Matsui、Ayato sato、Kazuhiro Hada、Yumi Tsuneura、Taku Nagai、Toshitaka Nabeshima、Kiyofumi Yamada
  • Organizer: CINP2021 VIRTUAL WORLD CONGRESS
  • Int'l Joint Research
• [Presentation] MK-801処置マウスの統合失調症様行動及び側坐核における神経伝達物質遊離に対するRhoキナーゼ阻害剤ファスジルの効果 (2021)
  • Author(s): 田中 里奈子、澤幡 雅仁、高瀨 冴子、Liu Yue、羽田 和弘、溝口 博之、永井 拓、鍋島 俊隆、尾崎 紀夫、山田 清文
  • Organizer: 第94回日本薬理学会年会