The mechanisms of social deficits caused by drug exposure via the womb

• Project/Area Number: 17K15765
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: MURAKAMI Hiroko 公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 研究員 (60619592)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 自閉症 / 社会性行動障害 / バルプロ酸 / エタノール / GABA / 薬物治療学

Outline of Final Research Achievements

The purpose of this study was to clarify the relationship between social behavioral deficits and the GABA signaling using two mice models prenatally exposed to valproic acid or ethanol. Administration of GABAA receptor inhibitors to these model mice showed improvement in social behavioral deficits. Abnormal expression of GABA-related genes was detected in mice exposed to valproic acid. We found that abnormal GABA signaling in utero affected social behavioral deficits.

Academic Significance and Societal Importance of the Research Achievements

本研究は、胎生期のGABAシグナル異常が生後の社会性行動障害に関連することを薬剤曝露による自閉症モデルマウスを用いて明らかにしたものである。これまでの先行研究において、生後脳における興奮／抑制のアンバランスは研究されてきたが、薬剤曝露による胎仔脳のGABAシグナルによる興奮／抑制のアンバランスに着目したものはなく、薬剤曝露による自閉症モデル動物に関して、新たな知見を得ることができ、社会性行動障害の病態解明と治療薬開発に貢献することが期待される。

Research Products

• [Journal Article] Study of effects of ifenprodil in patients with methamphetamine dependence: Protocol for an exploratory, randomized, double-blind, placebo-controlled trial. (2019)
  • Author(s): Kotajima-Murakami H, Takano A, Ogai Y, Tsukamoto S, Murakami M, Funada D, Tanibuchi Y, Tachimori H, Maruo K, Sasaki T, Matsumoto T, Ikeda K.
  • Journal Title: Neuropsychopharmacology Reports. Volume: － Issue: 2 Pages: 1-10
  • DOI: 10.1002/npr2.12050
  • Peer Reviewed / Open Access
• [Journal Article] Effects of rapamycin on social interaction deficits and gene expression in mice exposed to valproic acid in utero. (2019)
  • Author(s): Kotajima-Murakami H, Kobayashi T, Kashii H, Sato A, Hagino Y, Tanaka M, Nishito Y, Takamatsu Y, Uchino S, Ikeda K.
  • Journal Title: Mol Brain Volume: 12 Issue: 1 Pages: 3-3
  • DOI: 10.1186/s13041-018-0423-2
  • Peer Reviewed / Open Access
• [Journal Article] Brain hyperserotonemia causes autism-relevant social deficits in mice. (2018)
  • Author(s): Tanaka M, Sato A, Kasai S, Hagino Y, Kotajima-Murakami H, Kashii H, Takamatsu Y, Nishito Y, Inagaki M, Mizuguchi M, Hall FS, Uhl GR, Murphy D, Sora I, Ikeda K.
  • Journal Title: Mol Autism Volume: 9 Issue: 1 Pages: 60-60
  • DOI: 10.1186/s13229-018-0243-3
  • NAID: 120006543336
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] mTOR signaling pathway plays a key role in autism spectrum disorder. (2019)
  • Author(s): Kotajima H
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology
  • Int'l Joint Research / Invited
• [Presentation] The role of the cerebellum in fear-conditioned bradycardia. (2019)
  • Author(s): Kotajima H
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology
  • Int'l Joint Research
• [Presentation] Effects of rapamycin treatment on impaired social interaction and gene expression in mice treated prenatally with valproic acid. (2019)
  • Author(s): Kotajima H
  • Organizer: The 10th IBRO World Congress of Neuroscience (IBRO2019)
  • Int'l Joint Research
• [Presentation] 心拍制御の研究から精神疾患研究まで －心の解明を目指して－ (2018)
  • Author(s): 古田島(村上)浩子
  • Organizer: 第26回身体運動科学シンポジウム
  • Invited
• [Presentation] Rapamycin improves social deficits in the mice treated prenatally with valproic acid. (2018)
  • Author(s): Kotajima-Murakami H
  • Organizer: 57th American College of Neuropsychopharmacology (ACNP 2018)
  • Int'l Joint Research
• [Presentation] Rapamycin ameliorates impairment of social interaction in the mice exposed in utero to valproic acid. (2018)
  • Author(s): Kotajima-Murakami H
  • Organizer: 31st The International College of Neuropsychopharmacology World Congress (CINP2018)
  • Int'l Joint Research
• [Presentation] 覚せい剤依存症患者におけるイフェンプロジルの効果検討とfMRIを基点としたバイオマーカーの開発：二重盲検無作為化比較試験(研究プロトコル). (2018)
  • Author(s): 古田島(村上)浩子
  • Organizer: 第28回日本臨床精神神経薬理学会・第48回日本神経精神薬理学会 合同年会
• [Presentation] Rapamycin ameliorates impairment of social interaction in the mice exposed in utero to valproic acid (2018)
  • Author(s): Hiroko Kotajima-Murakami
  • Organizer: The International College of Neuropsychopharmacology (CINP)
• [Presentation] Inhibition of mTOR improves autism-like behaviors in mice in utero exposed to valproic acid (2017)
  • Author(s): Hiroko Kotajima-Murakami
  • Organizer: Asian College of Neuropsychopharmacology (5th AsCNP)
  • Int'l Joint Research
• [Presentation] 胎生期バルプロ酸曝露マウスの社会性行動障害のラパマイシン投与による改善 (2017)
  • Author(s): 古田島浩子
  • Organizer: 第39回日本生物学的精神医学会・第47回日本精神神経薬理学会
• [Presentation] mTOR阻害剤投与による胎生期バルプロ酸曝露マウスの自閉症様行動への影響 (2017)
  • Author(s): 村上（古田島）浩子
  • Organizer: 第40回日本分子生物学会年会・第90回日本生化学学会
• [Remarks] TOPICS 2017
  • URL: http://www.igakuken.or.jp/topics/2017/0429-2.html