Molecular pathology of schizophrenia and novel mechanisms of antipsychotics from the perspective of MIF

• Project/Area Number: 18K15483
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Kobe University
• Principal Investigator: Okazaki Satoshi 神戸大学, 医学部附属病院, 助教 (70722867)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 統合失調症 / MIF / アストロサイト / クロザピン / ヒストンアセチル化 / ES細胞 / iPS細胞 / 神経幹細胞 / ニューロン

Outline of Final Research Achievements

In order to elucidate the pathological mechanism of schizophrenia, we focused on macrophage migration inhibitory factor (MIF). We performed analysis using mouse-derived astrocytes. We observed increased MIF mRNA expression and protein production due to antipsychotics. We further investigated the details of the MIF expression mechanism using clozapine. We found that histone acetylation was involved in the mechanism. These findings suggest that MIF is involved in the pathophysiology of schizophrenia and the unknown action mechanism of antipsychotics. We are going to continue the investigation of the mechanism of MIF in schizophrenia using primary mouse ES cells and human iPS cells derived from patients with schizophrenia.

Academic Significance and Societal Importance of the Research Achievements

統合失調症は世界的に有病率約1%の主要な精神疾患であるが、生物学的基盤の詳細は現在も明らかでなく、診断・治療は未だ症状・経過に依存している。本研究により、統合失調症の分子病態および抗精神病薬の未知の作用機序におけるMIFの役割の一端が明らかになった。MIFに着目した統合失調症の研究は世界に先駆けており、学術的意義は高いと考える。また統合失調症の診断や治療応用に繋がる研究成果であり、社会的意義美も高いと考える。

Research Products

• [Journal Article] Clozapine increases macrophage migration inhibitory factor (MIF) expression via increasing histone acetylation of MIF promoter in astrocytes. (2021)
  • Author(s): Okazaki S, Boku S, Otsuka I, Horai T, Kimura A, Shimmyo N, Yamaki N, Hishimoto A.
  • Journal Title: J Psychiatr Res. Volume: 135 Pages: 237-242
  • DOI: 10.1016/j.jpsychires.2021.01.033
  • NAID: 120006996932
  • Peer Reviewed
• [Journal Article] Epigenetic Clock Analysis in Children With Fetal Alcohol Spectrum Disorder (2021)
  • Author(s): Okazaki Satoshi、Otsuka Ikuo、Shinko Yutaka、Horai Tadasu、Hirata Takashi、Yamaki Naruhisa、Sora Ichiro、Hishimoto Akitoyo
  • Journal Title: Alcoholism: Clinical and Experimental Research Volume: 45 Issue: 2 Pages: 329-337
  • DOI: 10.1111/acer.14532
  • Peer Reviewed
• [Journal Article] miR-19b is elevated in peripheral blood of schizophrenic patients and attenuates proliferation of hippocampal neural progenitor cells (2020)
  • Author(s): Horai T, Boku S, Okazaki S, Otsuka I, Ratta-Apha W, Mouri K, Yamaki N, Hirata T, Hishimoto A.
  • Journal Title: J Psychiatr Res . Volume: 131 Pages: 102-107
  • DOI: 10.1016/j.jpsychires.2020.09.006
  • NAID: 120006952760
  • Peer Reviewed
• [Journal Article] Decelerated Epigenetic Aging Associated With Mood Stabilizers in the Blood of Patients With Bipolar Disorder. (2020)
  • Author(s): Okazaki S, Numata S, Otsuka I, Horai T, Kinoshita M, Sora I, Ohmori T, Hishimoto A.
  • Journal Title: Translational Psychiatry Volume: 10 Issue: 1 Pages: 129-129
  • DOI: 10.1038/s41398-020-0813-y
  • NAID: 120006850492
  • Peer Reviewed / Open Access
• [Journal Article] ATP and Repetitive Electric Stimulation Increases Leukemia Inhibitory Factor Expression in Astrocytes: A Potential Role for Astrocytes in the Action Mechanism of Electroconvulsive Therapy (2020)
  • Author(s): Maruyama S, Boku S, Okazaki S, Kikuyama H, Mizoguchi Y, Monji A, Otsuka I, Sora I, Kanazawa T, Hishimoto A, Yoneda H.
  • Journal Title: Psychiatry Clin Neurosci . Volume: . Issue: 5 Pages: 12986-12986
  • DOI: 10.1111/pcn.12986
  • Peer Reviewed / Open Access
• [Journal Article] Chemokine Alterations in the Postmortem Brains of Suicide Completers (2020)
  • Author(s): Shinko Y, Otsuka I, Okazaki S, Horai T, Boku S, Takahashi M, Ueno Y, Sora I, Hishimoto A.
  • Journal Title: J Psychiatr Res . Volume: 120 Pages: 29-33
  • DOI: 10.1016/j.jpsychires.2019.10.008
  • Peer Reviewed / Open Access
• [Journal Article] Accelerated Extrinsic Epigenetic Aging and Increased Natural Killer Cells in Blood of Suicide Completers (2020)
  • Author(s): Okazaki S, Otsuka I, Horai T, Hirata T, Takahashi M, Ueno Y, Boku S, Sora I, Hishimoto A.
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry . Volume: 98 Pages: 109805-109805
  • DOI: 10.1016/j.pnpbp.2019.109805
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial DNA Copy Number Raises the Potential of Left Frontopolar Hemodynamic Response as a Diagnostic Marker for Distinguishing Bipolar Disorder From Major Depressive Disorder (2019)
  • Author(s): Tsujii N, Otsuka I, Okazaki S, Yanagi M, Numata S, Yamaki N, Kawakubo Y, Shirakawa O, Hishimoto A.
  • Journal Title: Front Psychiatry Volume: 10 Pages: 312-312
  • DOI: 10.3389/fpsyt.2019.00312
  • NAID: 120006869526
  • Peer Reviewed / Open Access
• [Journal Article] Major depressive disorder-associated SIRT1 locus affects the risk for suicide in women after middle age. (2019)
  • Author(s): Hirata T, Otsuka I, Okazaki S, Mouri K, Horai T, Boku S, Takahashi M, Ueno Y, Sora I, Shirakawa O, Hishimoto A.
  • Journal Title: Psychiatry Res Volume: 278 Pages: 141-145
  • DOI: 10.1016/j.psychres.2019.06.002
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association studies identify polygenic effects for completed suicide in the Japanese population. (2019)
  • Author(s): Otsuka I, Akiyama M, Shirakawa O, Okazaki S, Momozawa Y, Kamatani Y, Izumi T, Numata S, Takahashi M, Boku S, Sora I, Yamamoto K, Ueno Y, Toda T, Kubo M, Hishimoto A
  • Journal Title: Neuropsychopharmacology Volume: 44 Issue: 12 Pages: 2119-2124
  • DOI: 10.1038/s41386-019-0506-5
  • NAID: 120007027666
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic clock analysis of blood samples from Japanese schizophrenia patients. (2019)
  • Author(s): Okazaki S, Otsuka I, Numata S, Horai T, Mouri K, Boku S, Ohmori T, Sora I, Hishimoto A.
  • Journal Title: NPJ Schizophrenia Volume: 5 Issue: 1 Pages: 4-4
  • DOI: 10.1038/s41537-019-0072-1
  • NAID: 120006629323
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Investigation of chromosome Y loss in men with schizophrenia. (2018)
  • Author(s): Hirata T, Hishimoto A, Otsuka I, Okazaki S, Boku S, Kimura A, Horai T, Sora I.
  • Journal Title: Neuropsychiatr Dis Treat. Volume: 14 Pages: 2115-2122
  • DOI: 10.2147/ndt.s172886
  • NAID: 120006510199
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mitochondrial DNA copy number of peripheral blood in bipolar disorder: The present study and a meta-analysis. (2018)
  • Author(s): Yamaki N, Otsuka I, Numata S, Yanagi M, Mouri K, Okazaki S, Boku S, Horai T, Ohmori T, Shirakawa O, Sora I, Hishimoto A.
  • Journal Title: Psychiatry Research Volume: 269 Pages: 115-117
  • DOI: 10.1016/j.psychres.2018.08.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Accelerated extrinsic epigenetic aging and increased natural killer cells in blood of suicide completers (2021)
  • Author(s): S. Okazaki, I. Otsuka, T. Horai, T. Hirata, M. Takahashi, Y. Ueno, S. Boku, I. Sora, A. Hishimoto
  • Organizer: The International College of Neuropsychopharmacology (CINP) 2021 VIRTUAL WORLD CONGRESS
  • Int'l Joint Research
• [Presentation] メタボローム解析による統合失調症血液バイオマーカーの探究 (2020)
  • Author(s): 金 世賢, 岡崎 賢志, 大塚 郁夫, 新光 穣, 木村 敦, 蓬莱 政, 新名 尚史, 平田 尚士, 谷藤 貴紀, 山木 愛久, 青山 慎介, 菱本 明豊, 曽良 一郎
  • 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9回日本精神薬学会総会・学術集会合同年会
• [Presentation] 自殺完遂者の死後脳におけるケモカインの変化 (2020)
  • Author(s): 新光 穣, 大塚 郁夫, 岡崎 賢志, 蓬莱 政, 朴 秀賢, 高橋 玄倫, 上野 易弘, 曽良 一郎, 菱本 明豊
  • 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9回日本精神薬学会総会・学術集会合同年会
• [Presentation] ADHD患者由来の大脳皮質オルガノイドで見られた大脳皮質発達の遅延(Telencephalon organoid derived from ADHD patient showed delayed development of cerebral cortex) (2020)
  • Author(s): 張 丹夢, 江口 典臣, 岡崎 賢志, 曽良 一郎
  • 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9回日本精神薬学会総会・学術集会合同年会
• [Presentation] 統合失調症におけるマクロファージ遊走阻止因子(MIF)の血清濃度増加と遺伝子多型関連解析 (2019)
  • Author(s): 岡崎 賢志, 大塚 郁夫, 渡部 雄一郎, 朴 秀賢, 新名 尚史, 平田 尚士, 蓬莱 政, 染矢 俊幸, 曽良 一郎, 菱本 明豊
  • Organizer: 日本精神神経学会
• [Presentation] 統合失調症におけるY染色体モザイク欠損の検討 (2019)
  • Author(s): 平田 尚士, 菱本 明豊, 大塚 郁夫, 岡崎 賢志, 朴 秀賢, 木村 敦, 蓬莱 政, 曽良 一郎
  • Organizer: 日本精神神経学会
• [Presentation] 男性アルコール依存症患者の骨密度低下に関する横断的研究 (2019)
  • Author(s): 蓬莱 政, 菱本 明豊, 大塚 郁夫, 新名 尚史, 岡崎 賢志, 毛利 健太朗, 朴 秀賢, 曽良 一郎
  • Organizer: 日本精神神経学会
• [Presentation] 自殺既遂者の血液・脳組織におけるY染色体喪失の解析 (2019)
  • Author(s): 木村 敦, 菱本 明豊, 平田 尚士, 山本 愛久, 蓬莱 政, 新名 尚史, 大塚 郁夫, 岡崎 賢志, 朴 秀賢, 曽良 一郎
  • Organizer: 日本精神神経学会
• [Presentation] Mir-19b is increased in peripheral blood of schizophenic patients and a!ects proliferation and survival of hippocampal neural progenitor cells (2019)
  • Author(s): Boku S, Horai T, Okazaki S, Otsuka I, Mouri K, Hishimoto A
  • Organizer: Society for Neuroscience
  • Int'l Joint Research
• [Presentation] Mechanism of modified electroconvulsive therapy - electrical stimulation to neurogenesis (2018)
  • Author(s): Maruyama S, Boku S, Okazaki S, Kikuyama H, Kanazawa T, Yoneda H
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia (2018)
  • Author(s): Okazaki S, Otsuka I, Wanatabe Y, Numata S, Boku S, Shimmyo N, Ormori T, Someya T, Sora I, Hishimoto A
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Mosaic loss of chromosome Y in peripheral blood and its risk variants in men with schizophrenia (2018)
  • Author(s): Hirata T, Okazaki S, Otsuka I, Boku S, Aoyama S, Eguch N, Kimura A, Horai T, Sora I, Hishimoto A
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Loss of chromosome Y in blood, but not in brain, of suicide completers (2018)
  • Author(s): Otsuka I, Okazaki S, Kimura A, Horai T, Izumi T, Takahashi M, Ueno Y, Shirakawa O, Sora I, Hishimoto A
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] The cell cycle-related genes as biomarkers for schizophrenia (2018)
  • Author(s): Okazaki S, Boku S, Otsuka I, Eguchi N, Sora I, Hishimoto A
  • Organizer: Society for Neuroscience
  • Int'l Joint Research