Prevention and treatment strategies focusing on tryptophan metabolism, a common factor in the pathogenesis and pathophysiology hypothesis of schizophrenia.

• Project/Area Number: 20K07931
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Fujita Health University
• Principal Investigator: Mouri Akihiro 藤田医科大学, 保健学研究科, 教授 (20597851)
• Co-Investigator(Kenkyū-buntansha): 國澤 和生 藤田医科大学, 保健学研究科, 講師 (60780773) ; 鍋島 俊隆 藤田医科大学, 保健学研究科, 客員教授 (70076751)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: トリプトファン代謝 / キヌレニン-3-モノオキシゲナーゼ（KMO） / フェンサイクリジン（PCP） / ポリイノシン-ポリシチジン（PolyI:C） / 統合失調症 / キヌレン酸 / 3-ヒドロキシキヌレニン / PolyI:C / キヌレニン-3-モノオキシゲナーゼ / 酸化ストレス / 神経発達障害 / フェンサイクリジン / プレパルスインヒビション / モデル動物

Outline of Research at the Start

妊娠期のインフルエンザ感染がその出生児の統合失調症発症リスクを上昇させる。母体の免疫応答によるキヌレニン-3-モノオキシゲナーゼ（KMO）活性化が胎児の神経発達障害を惹起し、発症脆弱性を上昇させる可能性がある。一方、統合失調症患者の死後脳における研究ではKMO の活性低下と NMDA 受容体に対して拮抗作用を示すキヌレン酸の増加が認められている。 KMO 活性低下は統合失調症の病態に寄与する可能性がある。これら可能性を実験動物モデルで検証し、統合失調症の神経発達障害仮説およびグルタミン酸仮説における KMO を中心とするトリプトファン代謝経路の関与を解明し、予防法・治療法の開発をめざす。

Outline of Final Research Achievements

Mice lacking the kynurenine-3-monooxygenase (KMO) gene showed an increase in kynurenic acid, which aggravates phencyclidine (PCP)-induced behavioral abnormalities, and a decrease in xanthurenic acid and quinolinic acid, which ameliorate them, suggesting that the alteration of the TRP metabolic substrate due to reduced KMO activity is involved in the pathogenesis of schizophrenia. The results suggest that the alteration of TRP metabolic substrates by decreased KMO activity is involved in the severity of schizophrenia pathology.
When PolyI:C, which acts like viral RNA, is administered to pregnant mice, mice born from these dams show schizophrenia-like behavioral abnormalities. Maternal activation of KMO by PolyI:C produces 3-HK, which induces oxidative stress in the fetal brain, suggesting that it increases the vulnerability of the fetus to neurodevelopmental disorders and schizophrenia.

Academic Significance and Societal Importance of the Research Achievements

これまで統合失調症になった状態（病態）について仮説としてのグルタミン酸仮説、統合失調症になっていく過程（発症機序）についての仮説としての神経発達障害仮説がある。それぞれの仮説に基づき多くの研究が実施されてきたが、両仮説に共通した分子に注目した研究されてこなかった。本研究において統合失調症へのトリプトファン代謝経路の関与を明らかにしたことで、複雑な発症機序および病態メカニズムをシンプルに統一することができた。本成果による統合失調症の神経発達障害仮説およびグルタミン酸仮説におけるKMOを中心とするトリプトファン代謝経路の関与を解明が統合失調症の予防法・治療法の開発の一助となることを期待したい。

Research Products

• [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] Deficiency of kynurenine 3-monooxygenase exacerbates impairment of prepulse inhibition induced by phencyclidine (2022)
  • Author(s): Kubota Hisayoshi、Kunisawa Kazuo、Niijima Moe、Hirakawa Mami、Mori Yuko、Hasegawa Masaya、Fujigaki Suwako、Fujigaki Hidetsugu、Yamamoto Yasuko、Saito Kuniaki、Nabeshima Toshitaka、Mouri Akihiro
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 629 Pages: 142-151
  • DOI: 10.1016/j.bbrc.2022.09.003
  • Peer Reviewed
• [Journal Article] Memantine ameliorates the impairment of social behaviors induced by a single social defeat stress as juveniles (2022)
  • Author(s): Yoshida Mikio、Hasegawa Sho、Taniguchi Masayuki、Mouri Akihiro、Suzuki Chiharu、Yoshimi Akira、Mamiya Takayoshi、Ozaki Norio、Noda Yukihiro
  • Journal Title: Neuropharmacology Volume: 217 Pages: 109208-109208
  • DOI: 10.1016/j.neuropharm.2022.109208
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loureirin C and Xanthoceraside Attenuate Depression-Like Behaviors and Expression of Interleukin-17 in the Prefrontal Cortex Induced by Chronic Unpredictable Mild Stress in Mice (2022)
  • Author(s): Kunisawa Kazuo、Shan Jiajing、Lu Qiaohui、Yang Yang、Kosuge Aika、Kurahashi Hitomi、Saito Kuniaki、Zou Libo、Nabeshima Toshitaka、Mouri Akihiro
  • Journal Title: Neurochemical Research Volume: 47 Issue: 9 Pages: 2880-2889
  • DOI: 10.1007/s11064-022-03692-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Loureirin C and Xanthoceraside Prevent Abnormal Behaviors Associated with Downregulation of Brain Derived Neurotrophic Factor and AKT/mTOR/CREB Signaling in the Prefrontal Cortex Induced by Chronic Corticosterone Exposure in Mice (2022)
  • Author(s): Yang Yang、Mouri Akihiro、Lu Qiaohui、Kunisawa Kazuo、Kubota Hisayoshi、Hasegawa Masaya、Hirakawa Mami、Mori Yuko、Libo Zou、Saito Kuniaki、Nabeshima Toshitaka
  • Journal Title: Neurochemical Research Volume: 47 Issue: 9 Pages: 2865-2879
  • DOI: 10.1007/s11064-022-03694-x
  • Peer Reviewed / Int'l Joint Research
• [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] Targeting α6GABAA receptors as a novel therapy for schizophrenia: A proof-of-concept preclinical study using various animal models (2022)
  • Author(s): Lee Ming Tatt、Mouri Akihiro、Kubota Hisayoshi、Lee Hsin-Jung、Chang Man-Hsin、Wu Chen-Yi、Knutson Daniel E.、Mihovilovic Marko、Cook James、Sieghart Werner、Nabeshima Toshitaka、Chiou Lih-Chu
  • Journal Title: Biomedicine & Pharmacotherapy Volume: 150 Pages: 113022-113022
  • DOI: 10.1016/j.biopha.2022.113022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Duloxetine attenuates pain in association with downregulation of platelet serotonin transporter in patients with burning mouth syndrome and atypical odontalgia (2021)
  • Author(s): Nakamura Mariko、Yoshimi Akira、Mouri Akihiro、Tokura Tatsuya、Kimura Hiroyuki、Kishi Shinichi、Miyauchi Tomoya、Iwamoto Kunihiro、Ito Mikiko、Sato‐Boku Aiji、Ozaki Norio、Nabeshima Toshitaka、Noda Yukihiro
  • Journal Title: Human Psychopharmacology: Clinical and Experimental Volume: 37 Issue: 2
  • DOI: 10.1002/hup.2818
  • Peer Reviewed
• [Journal Article] Early postnatal inhibition of GLAST causes abnormalities of psychobehaviors and neuronal morphology in adult mice (2021)
  • Author(s): Uchida Mizuki、Noda Yukihiro、Hasegawa Sho、Hida Hirotake、Taniguchi Masayuki、Mouri Akihiro、Yoshimi Akira、Nabeshima Toshitaka、Yamada Kiyofumi、Aida Tomomi、Tanaka Kohichi、Ozaki Norio
  • Journal Title: Neurochemistry International Volume: 150 Pages: 105177-105177
  • DOI: 10.1016/j.neuint.2021.105177
  • Peer Reviewed
• [Journal Article] Heat-sterilized Bifidobacterium breve prevents depression-like behavior and interleukin-1β expression in mice exposed to chronic social defeat stress (2021)
  • Author(s): Kosuge Aika、Kunisawa Kazuo、Arai Satoshi、Sugawara Yumika、Shinohara Katsuki、Iida Tsubasa、Wulaer Bolati、Kawai Tomoki、Fujigaki Hidetsugu、Yamamoto Yasuko、Saito Kuniaki、Nabeshima Toshitaka、Mouri Akihiro
  • Journal Title: Brain, Behavior, and Immunity Volume: 96 Pages: 200-211
  • DOI: 10.1016/j.bbi.2021.05.028
  • Peer Reviewed
• [Journal Article] Multiple nicotinic acetylcholine receptor subtypes regulate social or cognitive behaviors in mice repeatedly administered phencyclidine (2021)
  • Author(s): Noda Yukihiro、Soeda Koki、Uchida Mizuki、Goto Sakika、Ito Takahiro、Kitagaki Shinji、Mamiya Takayoshi、Yoshimi Akira、Ozaki Norio、Mouri Akihiro
  • Journal Title: Behavioural Brain Research Volume: 408 Pages: 113284-113284
  • DOI: 10.1016/j.bbr.2021.113284
  • Peer Reviewed
• [Journal Article] Kynurenine 3-monooxygenase deficiency induces depression-like behavior via enhanced antagonism of α7 nicotinic acetylcholine receptors by kynurenic acid (2021)
  • Author(s): Mori Yuko、Mouri Akihiro、Kunisawa Kazuo、Hirakawa Mami、Kubota Hisayoshi、Kosuge Aika、Niijima Moe、Hasegawa Masaya、Kurahashi Hitomi、Murakami Reiko、Hoshi Masato、Nakano Takashi、Fujigaki Suwako、Fujigaki Hidetsugu、Yamamoto Yasuko、Nabeshima Toshitaka、Saito Kuniaki
  • Journal Title: Behavioural Brain Research Volume: 405 Pages: 113191-113191
  • DOI: 10.1016/j.bbr.2021.113191
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Involvement of PKCβI-SERT activity in stress vulnerability of mice exposed to twice-swim stress (2021)
  • Author(s): Ito Takahiro、Hiramatsu Yuka、Mouri Akihiro、Yoshigai Takuya、Takahashi Ayaki、Yoshimi Akira、Mamiya Takayoshi、Ozaki Norio、Noda Yukihiro
  • Journal Title: Neuroscience Research Volume: 171 Pages: 83-91
  • DOI: 10.1016/j.neures.2021.01.002
  • Peer Reviewed
• [Journal Article] Pharmacological blockade of dopamine D1- or D2-receptor in the prefrontal cortex induces attentional impairment in the object-based attention test through different neuronal circuits in mice (2021)
  • Author(s): Wulaer Bolati、Kunisawa Kazuo、Tanabe Moeka、Yanagawa Aika、Saito Kuniaki、Mouri Akihiro、Nabeshima Toshitaka
  • Journal Title: Molecular Brain Volume: 14 Issue: 1 Pages: 43-43
  • DOI: 10.1186/s13041-021-00760-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Preventive role of regular low-intensity exercise during adolescence in schizophrenia model mice with abnormal behaviors (2021)
  • Author(s): Koizumi Hikaru、Hiraga Taichi、Oharomari Leandro K.、Hata Toshiaki、Shima Takeru、Yook Jang Soo、Okamoto Masahiro、Mouri Akihiro、Nabeshima Toshitaka、Soya Hideaki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 534 Pages: 610-616
  • DOI: 10.1016/j.bbrc.2020.11.032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prefrontal cortex, dorsomedial striatum, and dentate gyrus are necessary in the object-based attention test in mice (2020)
  • Author(s): Wulaer Bolati、Kunisawa Kazuo、Kubota Hisayoshi、Suento Willy Jaya、Saito Kuniaki、Mouri Akihiro、Nabeshima Toshitaka
  • Journal Title: Molecular Brain Volume: 13 Issue: 1 Pages: 391-391
  • DOI: 10.1186/s13041-020-00711-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Focal loss of the paranodal domain protein Neurofascin155 in the internal capsule impairs cortically induced muscle activity in vivo (2020)
  • Author(s): Kunisawa Kazuo、Hatanaka Nobuhiko、Shimizu Takeshi、Kobayashi Kenta、Osanai Yasuyuki、Mouri Akihiro、Shi Qian、Bhat Manzoor A.、Nambu Atsushi、Ikenaka Kazuhiro
  • Journal Title: Molecular Brain Volume: 13 Issue: 1 Pages: 159-159
  • DOI: 10.1186/s13041-020-00698-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prefrontal cortex miR‐874‐3p prevents lipopolysaccharide‐induced depression‐like behavior through inhibition of indoleamine 2,3‐dioxygenase 1 expression in mice (2020)
  • Author(s): Suento Willy Jaya、Kunisawa Kazuo、Wulaer Bolati、Kosuge Aika、Iida Tsubasa、Fujigaki Suwako、Fujigaki Hidetsugu、Yamamoto Yasuko、Tanra Andi Jayalangkara、Saito Kuniaki、Mouri Akihiro、Nabeshima Toshitaka
  • Journal Title: Journal of Neurochemistry Volume: - Issue: 6 Pages: 1963-1978
  • DOI: 10.1111/jnc.15222
  • NAID: 130008001606
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Shati/Nat8l deficiency disrupts adult neurogenesis and causes attentional impairment through dopaminergic neuronal dysfunction in the dentate gyrus (2020)
  • Author(s): Wulaer Bolati、Kunisawa Kazuo、Hada Kazuhiro、Jaya Suento Willy、Kubota Hisayoshi、Iida Tsubasa、Kosuge Aika、Nagai Taku、Yamada Kiyofumi、Nitta Atsumi、Yamamoto Yasuko、Saito Kuniaki、Mouri Akihiro、Nabeshima Toshitaka
  • Journal Title: Journal of Neurochemistry Volume: 157 Issue: 3 Pages: 642-655
  • DOI: 10.1111/jnc.15022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hispidulin attenuates the social withdrawal in isolated disrupted‐in‐schizophrenia‐1 mutant and chronic phencyclidine‐treated mice (2020)
  • Author(s): Mouri Akihiro、Lee Hsin‐Jung、Mamiya Takayoshi、Aoyama Yuki、Matsumoto Yurie、Kubota Hisayoshi、Huang Wei‐Jan、Chiou Lih‐Chu、Nabeshima Toshitaka
  • Journal Title: British Journal of Pharmacology Volume: 177 Issue: 14 Pages: 3210-3224
  • DOI: 10.1111/bph.15043
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] シンポジウム1精神疾患の発症・病態における免疫・炎症・酸化ストレスの関与：母体免疫活性化による胎児脳形成異常・行動変化におけるトリプトファン代謝の関与. (2021)
  • Author(s): 毛利 彰宏, 國澤 和生, 齋藤 邦明, 鍋島俊隆.
  • Organizer: 第43回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.
• [Presentation] 慢性予測不能軽度ストレスによるミクログリアに関連したキヌレニン代謝の変容に対するニコチンの作用. (2021)
  • Author(s): 毛利彰宏、齋藤邦明
  • 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] MAGE-D1遺伝子欠損マウスに認められるうつ様行動はノルアドレナリントランスポーターのリン酸化低下を伴う (2021)
  • Author(s): 毛利 彰宏、平川 茉実、國澤 和生、渡辺 研、窪田悠力 、木村 真理、森 優子、野田 幸裕、齋藤 邦明、鍋島 俊隆
  • Organizer: 第15回日本臨床検査学教育学会学術大会
• [Presentation] キノリン酸代謝の低下はタウのリン酸化を亢進し、脳室拡大とドパミン神経期の低下と共に運動・認知機能の障害を惹起する (2021)
  • Author(s): 毛利 彰宏、新島 萌、 國澤 和生、高野 一輝、山田 雅之、 勅使河原 知明、窪田 悠力 、平川 茉実、 森 優子、 星 雅人、 藤垣 英嗣、 山本 康子、 長谷川 眞也、倉橋 仁美、齋藤 邦明、 鍋島 俊隆
  • Organizer: 第43回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
• [Presentation] QPRT Deficit Leads Motor and Cognitive Dysfunction through Increase of Oxidative stress in the Dopaminergic Neurvous System by Quinolinic Acid. (2021)
  • Author(s): Akihiro Mouri, Moe Niijima, Kazuo Kunisawa, Takano Kazuki, Masayuki Yamada, Romoaki Teshigawara, Hisayoshi Kubota, Mami Hirakawa, Yuko Mori, Masato Hoshi, Fujigaki Hidetsugu, Yasuko Yamamoto, Masaya Hasegawa, Hitomi Kurahashi, Kuniaki Saito, Toshitaka Nabeshimai
  • Organizer: 第64回日本神経化学会大会
• [Presentation] QPRT deficit leads motor and cognitive dysfunction through tau phosphorylation and oxidative stress in the dopaminergic neuronal system by quinolinic acid (2021)
  • Author(s): Akihiro Mouri, Moe Niijima, Tomoaki Teshigawara, Kazuo Kunisawa, Hisayoshi Kubota, Mami Hirakawa, Yuko Mori, Masato Hoshi, Yasuko Yamamoto, Toshitaka Nabeshima, Kuniaki Saito
  • Organizer: The International College of Neuropsychopharmacology 2021
  • Int'l Joint Research
• [Presentation] Chronic social defeat stress induces depression-like behaviors caused by myelin abnormalities in the corpus callosum through microglial activation (2021)
  • Author(s): Kazuo Kunisawa, Tsubasa Iida, Sugawara Yumika, Sei Saitoh, Aika Kosuge, Bolati Wulaer, Yasuko Yamamoto, Kuniaki Saito, Toshitaka Nabeshima, Akihiro Mouri.
  • Organizer: The International College of Neuropsychopharmacology 2021
  • Int'l Joint Research
• [Presentation] Chronic social defeat stress induces depression-like behavior through the decrease of GLT-1 ubiquitination in the mouse prefrontal cortex. (2021)
  • Author(s): Aika Kosuge, Kazuo Kunisawa, Tsubasa Iida, Bolati Wulaer, Willy Jaya Suento, Yasuko Yamamoto, Kuniaki Saito, Akihiro Mouri, Toshitaka Nabeshima.
  • Organizer: The International College of Neuropsychopharmacology 2021
  • Int'l Joint Research
• [Presentation] Deficiency of kynurenine 3-monooxygenase increases vulnerability to the PCP-induced behavioral abnormalities. (2021)
  • Author(s): Hisayoshi Kubota, Akihiro Mouri, Kazuo Kunisawa, Moe Niijima, Mami Hirakawa, Yuko Mori, Yasuko Yamamoto, Kuniaki Saito, Toshitaka Nabeshima.
  • Organizer: The International College of Neuropsychopharmacology 2021
  • Int'l Joint Research
• [Presentation] 胎生期PolyI:C曝露による統合失調症様モデルとキヌレニン代謝の関与 (2020)
  • Author(s): 毛利彰宏、國澤和生、齋藤邦明、鍋島俊隆
  • Organizer: 第50回日本神経精神薬理学会年会・第42回日本生物学的精神医学会年会・第4回日本精神薬学会総会（NPBPPP2020合同年会）
• [Book] visual core pharma 薬物治療学（分担執筆）：Ⅲ章 疾患と薬物治療 84，薬物依存 (2021)
  • Author(s): 毛利彰宏、野田幸裕
  • Total Pages: 6
  • Publisher: 南山堂
  • ISBN: 9784525720506