Study on development of novel antipsychotics based on reverse translational research

• Project/Area Number: 20K07082
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Fujita Health University
• Principal Investigator: Nagai Taku 藤田医科大学, その他部局等, 教授 (10377426)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 統合失調症 / 遺伝子変異 / マウス / コピー数多型

Outline of Research at the Start

統合失調症は、陽性症状、陰性症状および認知機能障害を示す重大な精神疾患であり、現在の治療では十分な効果が得られない難治例も多い。現在、精神疾患の診断は精神症候学に依拠しており、病態を反映した客観的な診断法はなく、治療法の開発も遅れている。統合失調症の発症に関する遺伝的寄与は大きいと推測されているが、発症メカニズムの詳細は未だ不明である。統合失調症の発症に強く関連するコピー数多型（CNV）としてARHGAP10を含む多数の遺伝子が日本人の統合失調症患者で同定されている。本研究課題では、統合失調症患者と同様の遺伝子変異を有する新規モデルマウスの包括的解析を実施し、新規治療薬の基盤を提示する。

Outline of Final Research Achievements

We recently found a significant association between exonic copy-number variations in the Rho GTPase activating protein 10 (Arhgap10) gene and schizophrenia in Japanese patients. Accordingly, we generated a mouse model (Arhgap10 mutant mice) carrying a missense variant and a coexisting frameshift mutation. The expression levels of phosphorylated MYPT-1 and PAK1/2 in the striatum and nucleus accumbens (NAc) were increased in Arhgap10 mutant mice compared with wild-type littermates. Arhgap10 mutant mice exhibited an increase in neuronal complexity and spine density in the striatum and NAc. The number of c-Fos-positive cells was significantly increased after methamphetamine treatment in the dorsomedial striatum and NAc core of Arhgap10 mutant mice. These results suggested that schizophrenia-associated Arhgap10 gene mutations result in morphological abnormality of neurons in the striatum and NAc.

Academic Significance and Societal Importance of the Research Achievements

統合失調症は、重大な精神疾患であり、現在の治療では十分な効果が得られない難治例も多い。現在、精神疾患の診断は精神症候学に依拠しており、病態を反映した客観的な診断法はなく、治療法の開発も遅れている。統合失調症の発症に関する遺伝的寄与は大きいと推測されているが、発症メカニズムの詳細は未だ不明であり、病態に基づく治療薬開発が進んでいないのが現状である。本研究課題では、神経化学、形態学および行動薬理学を融合させた包括的解析を実施することにより統合失調症患者で同定されたARHGAP10遺伝子変異の病態生理学的意義を明らかにすることができた。Rhoシグナルを標的とした新規治療薬の開発に繋がる成果を示した。

Research Products

• [Journal Article] DARPP-32/protein phosphatase 1 regulates Rasgrp2 as a novel component of dopamine D1 receptor signaling in striatum. (2023)
  • Author(s): Kuroiwa, M., Shuto, T., Nagai, T., Amano, M., Kaibuchi, K., Nairn, A.C., Nishi, A.
  • Journal Title: Neurochem. Int. Volume: 162 Pages: 105438-105438
  • DOI: 10.1016/j.neuint.2022.105438
  • Peer Reviewed
• [Journal Article] An evaluation method for developing abuse-deterrent opioid formulations with agonist and antagonist combinations using conditioned place preference. (2023)
  • Author(s): Zhang, X., Kitaichi, K., Mouri A., Zhou, X., Nabeshima, T., Yamada, K., Nagai, T.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 639 Pages: 100-105
  • DOI: 10.1016/j.bbrc.2022.11.072
  • Peer Reviewed / Int'l Joint Research
• [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] 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] Clinical impact of standardized creatinine on dose adjustment of capecitabine (2022)
  • Author(s): Ito, A., Ichikawa, K., Miyazaki, M., Sagara, A., Motegi, T., Ando, Y., Senzaki, K., Nagai, T., Yamada K.
  • Journal Title: Nagoya Journal of Medical Science Volume: 84 Issue: 3 Pages: 547-553
  • DOI: 10.18999/nagjms.84.3.547
  • ISSN: 0027-7622
  • URL: https://nagoya.repo.nii.ac.jp/records/2003747
  • Peer Reviewed / Open Access
• [Journal Article] Phosphoproteomic of the acetylcholine pathway enables discovery of the PKC-β-PIX-Rac1-PAK cascade as a stimulatory signal for aversive learning (2022)
  • Author(s): Yamahashi Y, Lin YH, Mouri A, Iwanaga S, Kawashima K, Tokumoto Y, Watanabe Y, Faruk MO, Zhang X, Tsuboi D, Nakano T, Saito N, Nagai T, Yamada K, Kaibuchi K.
  • Journal Title: Molecular Psychiatry Volume: 27 Issue: 8 Pages: 3479-3492
  • DOI: 10.1038/s41380-022-01643-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Dopamine drives neuronal excitability via KCNQ channel phosphorylation for reward behavior (2022)
  • Author(s): Tsuboi Daisuke、Otsuka Takeshi、Shimomura Takushi、Faruk Md Omar、Yamahashi Yukie、Amano Mutsuki、Funahashi Yasuhiro、Kuroda Keisuke、Nishioka Tomoki、Kobayashi Kenta、Sano Hiromi、Nagai Taku、Yamada Kiyofumi、Tzingounis Anastasios V.、Nambu Atsushi、Kubo Yoshihiro、Kawaguchi Yasuo、Kaibuchi Kozo
  • Journal Title: Cell Reports Volume: 40 Issue: 10 Pages: 111309-111309
  • DOI: 10.1016/j.celrep.2022.111309
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Muscarinic signaling regulates voltage‐gated potassium channel KCNQ2 phosphorylation in the nucleus accumbens via protein kinase C for aversive learning (2021)
  • Author(s): Faruk Md. Omar、Tsuboi Daisuke、Yamahashi Yukie、Funahashi Yasuhiro、Lin You‐Hsin、Ahammad Rijwan Uddin、Hossen Emran、Amano Mutsuki、Nishioka Tomoki、Tzingounis Anastasios V、Yamada Kiyofumi、Nagai Taku、Kaibuchi Kozo
  • Journal Title: Journal of Neurochemistry Volume: 160 Issue: 3 Pages: 325-341
  • DOI: 10.1111/jnc.15555
  • Peer Reviewed / Open Access
• [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] 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] Accumbal D2R-medium spiny neurons regulate aversive behaviors through PKA-Rap1 pathway. (2020)
  • Author(s): Lin, Y-H., Yamahashi, Y., Kuroda, K., Faruk M. O., Zhang, X., Yamada, K., Yamanaka, A., Nagai, T., Kaibuchi, K.
  • Journal Title: Neurocham. Int. Volume: 143 Pages: 104935-104935
  • DOI: 10.1016/j.neuint.2020.104935
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive analysis of a novel mouse model of the 22q11.2 deletion syndrome: a model with the most common 3.0-Mb deletion at the human 22q11.2 locus (2020)
  • Author(s): Saito Ryo、Koebis Michinori、Nagai Taku、Shimizu Kimiko、Liao Jingzhu、Wulaer Bolati、Sugaya Yuki、Nagahama Kenichiro、Uesaka Naofumi、Kushima Itaru、Mori Daisuke、Maruyama Kazuaki、Nakao Kazuki、Kurihara Hiroki、Yamada Kiyofumi、Kano Masanobu、Fukada Yoshitaka、Ozaki Norio、Aiba Atsu
  • Journal Title: Translational Psychiatry Volume: 10 Issue: 1 Pages: 35-35
  • DOI: 10.1038/s41398-020-0723-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation and analysis of novel Reln-deleted mouse model corresponding to exonic Reln deletion in schizophrenia (2020)
  • Author(s): Masahito Sawahata, Daisuke Mori, Yuko Arioka, Hisako Kubo, Itaru Kushima, Kanako Kitagawa, Akira Sobue, Emiko Shishido, Mariko Sekiguchi, Akiko Kodama, Ryosuke Ikeda, Branko Aleksic, Hiroki Kimura, Kanako Ishizuka, Taku Nagai, Kozo Kaibuchi, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki
  • Journal Title: Psychiatry and clinical neurosciences Volume: 1 Issue: 5 Pages: 1-10
  • DOI: 10.1111/pcn.12993
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] AUTS2 regulation of synapses for proper synaptic inputs and social communication. (2020)
  • Author(s): Hori Kei、Yamashiro Kunihiko、Nagai Taku、... Yamada Mitsuhiko、Yamada Kiyofumi、Hoshino Mikio
  • Journal Title: iScience Volume: ー Issue: 6 Pages: 101183-101183
  • DOI: 10.1016/j.isci.2020.101183
  • Peer Reviewed / Open Access
• [Journal Article] ARHGAP10, which encodes Rho GTPase-activating protein 10, is a novel gene for schizophrenia risk (2020)
  • Author(s): Mariko Sekiguchi, Akiko Kodama,... Emiko Shishido,... Daisuke Mori, Norio Ozaki
  • Journal Title: Translational psychiatry Volume: 10 Issue: 1 Pages: 1-15
  • DOI: 10.1038/s41398-020-00917-z
  • 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
• [Presentation] 知ってそうで知らなかった精神神経薬：ドパミンの働きと抗精神病薬の使い方. (2022)
  • Author(s): 永井拓
  • Organizer: 第96回日本薬理学会年会／第43回日本臨床薬理学会
  • Invited
• [Presentation] オピオイド受容体拮抗薬を配合した乱用抵抗性製剤の効果に関する薬理学的検討. (2022)
  • Author(s): 永井拓, 張心健, 山田清文
  • Organizer: 第57回日本アルコール・アディクション医学会学術総会（アルコール・薬物依存関連学会 合同学術総会）
  • Invited
• [Presentation] Accumbal D2R-medium spiny neurons regulate aversive behaviors through PKA-Rap1 pathway. (2022)
  • Author(s): Nagai T, Lin Y-H, Yamahashi Y, Kuroda K, Faruk MO, Zhang X, Kaibuchi K.
  • Organizer: 4th Japan-UK Neuroscience Symposium 2022.
  • Int'l Joint Research / Invited
• [Presentation] PKA-Rap1 pathway in the nucleus accumbens regulates emotional behaviors of mice. (2022)
  • Author(s): Nagai T.
  • Organizer: The 1st Fujita International Symposium on Brain Science.
  • Int'l Joint Research / Invited
• [Presentation] 快・不快を生み出す脳内分子メカニズム (2021)
  • Author(s): 永井拓
  • Organizer: 第43回日本生物学的精神医学会・第51回日本神経精神薬理学会合同年会
  • Invited
• [Presentation] 情動行動とタンパク質リン酸化 (2021)
  • Author(s): 永井拓
  • Organizer: 第94回日本生化学会大会
  • Invited
• [Presentation] コカインにより惹起されるリン酸化シグナルの解明 (2021)
  • Author(s): 永井拓
  • Organizer: 2021年度アルコール・薬物依存関連学会合同学術総会
  • Invited
• [Presentation] 情動行動の発現に関与する脳内シグナル伝達機構 (2021)
  • Author(s): 永井拓
  • Organizer: 2021年度生理学研究所研究会
  • Invited
• [Presentation] 客観的な診断に基づく統合失調症の新規治療法の開発 (2020)
  • Author(s): 永井拓, 尾崎紀夫, 山田清文.
  • Organizer: 第30回日本医療薬学会年会
• [Presentation] 次世代を担う若き医療薬科学研究者達へ繋ぐバトン：恩師からのメッセージ (2020)
  • Author(s): 永井拓
  • Organizer: 第14回次世代を担う若手のための医療薬科学シンポジウム
  • Invited
• [Presentation] 精神疾患の新規薬物療法を目指したリバーストランスレーショナルリサーチ (2020)
  • Author(s): 永井拓
  • Organizer: 第41回日本臨床薬理学会学術総会
  • Invited
• [Remarks] 藤田医科大学 精神・神経病態解明センター神経行動薬理学研究部門ホームページ
  • URL: https://www.fujita-hu.ac.jp/icbs/behav-neuropharmacol/
• [Remarks] 藤田医科大学 精神・神経病態解明センターホームページ
  • URL: https://www.fujita-hu.ac.jp/icbs/