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The involvement of abnormal histone modification in schizophrenia-related behaviors in rodent models

Research Project

Project/Area Number 21K03136
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 10040:Experimental psychology-related
Research InstitutionNational Center of Neurology and Psychiatry

Principal Investigator

Furuie Hiroki  国立研究開発法人国立精神・神経医療研究センター, 精神保健研究所 精神薬理研究部, 室長 (90639105)

Co-Investigator(Kenkyū-buntansha) 山田 光彦  国立研究開発法人国立精神・神経医療研究センター, 精神保健研究所 精神薬理研究部, 客員研究員 (60240040)
三輪 秀樹  国立研究開発法人国立精神・神経医療研究センター, 精神保健研究所 精神薬理研究部, 室長 (80468488)
國石 洋  国立研究開発法人国立精神・神経医療研究センター, 精神保健研究所 精神薬理研究部, 特別研究員 (60805034)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords統合失調症 / エピジェネティクス / ヒストン脱アセチル化酵素 / グルタミン酸脱炭酸酵素 / ヒストン修飾 / GABA / ヒストンアセチル化 / ラット / 動物モデル
Outline of Research at the Start

本研究では、統合失調症におけるHDAC増加とGABA機能障害および多様な精神症状の因果関係を明らかにする。そのため、複数の統合失調症モデル動物を作成し、これらの動物でHDACが増加しているか、GABA機能が低下しているか検証する。また、人工的にHDACを過剰発現させた場合に、GABA機能の低下と統合失調症様行動が生じるかどうか調べる。続いて、HDAC阻害剤が、GABA機能と統合失調症様行動を改善できるか検証する。さらに、HDAC阻害剤がGABA機能の亢進を介して行動異常を改善する可能性について調べるため、GABA合成酵素を持たない動物においてもHDAC阻害剤が治療的効果を示すのか検討する。

Outline of Final Research Achievements

In this study, we investigated the involvement of abnormal histone modification in schizophrenia-like behaviors and hypofunction of GABAergic transmission induced by decrease in glutamate decarboxylase (GAD) expression. As a result, we found that the number of GAD67-positive neurons and Gad1 mRNA expressions were decreased in the brain of rats subjected to neonatal NMDA receptor blockade, a rodent model of schizophrenia. On the other hand, repeated administration of histone deacetylase inhibitor ameliorated the memory impairment induced by neonatal NMDA receptor blockade without affecting the expression of Gad1 mRNA. Unfortunately, this study could not demonstrate the involvement of alterations in histone modification in both schizophrenia-like behaviors and GABAergic hypofunction. However, the results suggest that histone deacetylase inhibitors may be a novel therapeutic strategy for schizophrenia.

Academic Significance and Societal Importance of the Research Achievements

統合失調症の生物学的メカニズムについて現状では不明な点が多く、有効な治療法も確立されていない。本研究の結果は、前頭前皮質や海馬におけるGABA機能低下が統合失調症様行動をもたらすという仮説を支持している。また本研究において、ヒストン脱アセチル化酵素の阻害が統合失調症モデル動物の記憶障害を改善したことから、従来の抗精神病薬が効果を示さない統合失調症の認知機能障害に対するヒストン脱アセチル化酵素阻害剤の有効性が示唆される。本研究の成果は、統合失調症の生物学的背景の理解に重要な示唆を与えるとともに、新規治療薬の研究開発に貢献できるものと期待される。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (20 results)

All 2023 2022 2021 Other

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 2 results) Presentation (14 results) (of which Int'l Joint Research: 4 results) Remarks (1 results)

  • [Journal Article] Effects of riluzole on psychiatric disorders with anxiety or fear as primary symptoms: A systematic review.2023

    • Author(s)
      Yoshitaka Kawashima, Misa Yamada, Hiroki Furuie, Hiroshi Kuniishi, Kie Akagi, Tomoko Kawashima, Takamasa Noda, Mitsuhiko Yamada
    • Journal Title

      Neuropsychopharmacology reports

      Volume: 43 Issue: 3 Pages: 320-327

    • DOI

      10.1002/npr2.12364

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hydrogen sulfide and polysulfides induce GABA/glutamate/d-serine release, facilitate hippocampal LTP, and regulate behavioral hyperactivity2023

    • Author(s)
      Hiroki Furuie#、Yuka Kimura#、Tatsuhiro Akaishi#、Misa Yamada、Yoshiki Miyasaka、Akiyoshi Saitoh、Norihiro Shibuya、Akiko Watanabe、Naoki Kusunose、Tomoji Mashimo、Takeo Yoshikawa、Mitsuhiko Yamada、Kazuho Abe、Hideo Kimura
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 1-19

    • DOI

      10.1038/s41598-023-44877-y

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characterization of a WD-repeat family protein WDR3 in the brain of WDR3 hetero knockout mice.2023

    • Author(s)
      Tanabe-Kobayashi, Furuie, Misa Yamada, Mitsuhiko Yamada.
    • Journal Title

      Brain Research

      Volume: 1800 Pages: 148188-148188

    • DOI

      10.1016/j.brainres.2022.148188

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] An emotional stress model using witnessing social defeat scenes in mice2023

    • Author(s)
      中武優子、古家宏樹、山田光彦.
    • Journal Title

      Folia Pharmacologica Japonica

      Volume: 158 Issue: 1 Pages: 39-42

    • DOI

      10.1254/fpj.22104

    • ISSN
      0015-5691, 1347-8397
    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Neonatal blockade of NR2A-containing but not NR2B-containing NMDA receptor induces spatial working memory deficits in adult rats2022

    • Author(s)
      Furuie Hiroki、Yamada Mitsuhiko
    • Journal Title

      Neuroscience Research

      Volume: 176 Pages: 57-65

    • DOI

      10.1016/j.neures.2021.10.005

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] Social facilitation of feeding behavior in a schizophrenia rat model.2023

    • Author(s)
      Furuie H, Ukezono M, Okada T, Yamada M
    • Organizer
      The 11th Congress pf the Asian Society for Child and Adolescent Psychiatry and Allid Professions (ASCAPAP) 2023,
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The effect of lesion in the anterior cungulate cortex on social facilitation in rat.2023

    • Author(s)
      Ukezono M, Takano Y, Furuie H, Nakatake Y, Shirakawa Y, Sayuri H Egashira Y, Uono S, Takada M Okada T
    • Organizer
      The 11th Congress pf the Asian Society for Child and Adolescent Psychiatry and Allid Professions (ASCAPAP) 2023,
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Subchoronic treatment with MK-801 during neonatal period decreased social interaction in adult rats.2023

    • Author(s)
      Furuie H, Nakatake Y
    • Organizer
      Society for Neuroscience Annual Meeting 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The involvement of the oxytocin signaling in the transmission of social stress in mice.2023

    • Author(s)
      Nakatake Y, Furuie H, Inoue YU, Inoue T, Yoshizawa K, Yamada M
    • Organizer
      Society for Neuroscience Annual Meeting 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 新生仔期MK-801投与ラットの社会的相互作用を障害する.2023

    • Author(s)
      古家宏樹,中武優子
    • Organizer
      第53回日本神経精神薬理学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Developmental stage-specific involvement of NMDA receptor hypofunction in risk formation for psychiatric disorders.2022

    • Author(s)
      Furuie H, Yamada M.
    • Organizer
      第96回日本薬理学会年会
    • Related Report
      2022 Research-status Report
  • [Presentation] 視覚情報を利用したマウスの新規ストレスモデル.2022

    • Author(s)
      中武優子、古家宏樹、請園正敏、山田美佐、吉澤一巳、山田光彦.
    • Organizer
      BPCNPNPPP
    • Related Report
      2022 Research-status Report
  • [Presentation] 新生仔期NMDA 受容体慢性遮断はラットの食餌行動の社会的促進を障害する.2022

    • Author(s)
      古家宏樹、請園正敏、岡田俊、山田光彦.
    • Organizer
      第40回日本生理心理学会大会
    • Related Report
      2022 Research-status Report
  • [Presentation] NMDA型グルタミン酸受容体遮断はラットのSense of Agencyを減衰させる.2022

    • Author(s)
      寺尾真実、古家宏樹、山田光彦、澤幸祐.
    • Organizer
      日本心理学会第86回大会
    • Related Report
      2022 Research-status Report
  • [Presentation] NMDA受容体NR2Aサブユニットのラット新生仔期における機能阻害は空間作業記憶の発達を障害する.2022

    • Author(s)
      山田光彦、古家宏樹.
    • Organizer
      第118回日本精神神経学会学術総会、第118回日本精神神経学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] A psychosocial stress model using withnessing social defeat scenes.2022

    • Author(s)
      Nakatake Y, Furuie H, Inoue-Ueno Y, Inoue T, Yosizawa K, Hosino M, Yamada M
    • Organizer
      第95回日本薬理学会年会
    • Related Report
      2021 Research-status Report
  • [Presentation] Neonatal blockade of NR2A-containing NMDA receptor induces schizophrenia-related behaviors in adult rats.2022

    • Author(s)
      Furuie H, Yamada M
    • Organizer
      第95回日本薬理学会年会
    • Related Report
      2021 Research-status Report
  • [Presentation] The oxytocin signaling in the anterior insular cortex mediates the emotional contagion in mice.2021

    • Author(s)
      中武優子, 古家宏樹, 吉澤一巳, 山田光彦
    • Organizer
      第44回日本神経科学大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 不安を主症状とする精神疾患に対するRiluzoleの効果:システマティックレビューによる検討.2021

    • Author(s)
      山田光彦, 川島義高, 山田美佐, 古家宏樹, 國石洋, 立花良之, 野田隆政
    • Organizer
      第42回日本臨床薬理学会学術総会
    • Related Report
      2021 Research-status Report
  • [Remarks] 記憶促進と統合失調症様行動抑制を発見 ―硫化水素とポリサルファイドの神経伝達物質放出制御を明らかに―

    • URL

      https://www.ncnp.go.jp/topics/2023/20231031p2.html

    • Related Report
      2023 Annual Research Report

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Published: 2021-04-28   Modified: 2025-01-30  

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