Study of the Mechanisms by Which Behavioral Therapy Improves Impairment of Social Interaction in ASD

• Project/Area Number: 19K16902
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51020:Cognitive and brain science-related
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: KOTAJIMA 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, 主任研究員 (60619592)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 自閉スペクトラム症 / 行動療法 / DNAメチル化 / 社会性行動 / エピジェネティクス / 自閉症

Outline of Research at the Start

自閉症の中核症状は社会性障害である。現在、自閉症患者の社会性障害に対する薬剤治療法は存在せず行動療法が治療として行われており、開始年齢が早いほど効果的である。しかしながら、自閉症の社会性障害が行動療法によって、どのようなメカニズムで改善するかは明らかでない。一方で、不安障害児を対象とした研究において行動療法がDNAメチル化に影響することが示された。本研究は単一遺伝子疾患の自閉症モデルマウスの中でも自閉症を高い確率で発症する結節性硬化症（TSC）のモデルマウス（Tsc1+/-マウス）を用いてDNAメチル化に着目することで、自閉症における行動療法の影響および効果を検討する。

Outline of Final Research Achievements

This study examined the effects of peer-rearing on autism spectrum disorders (ASD)-like behaviors in tuberous sclerosis (TSC) model mice, using peer-rearing with wild-type mice as a behavioral therapy of ASD, and analyzed DNA methylation. Tsc1+/- mice showed improved impairment of social interaction when living with wild-type mice from 3 weeks of age. We also found that the pattern of DNA methylation may differ depending on the genotype and peer-rearing. Genes that were found to be involved in development and protein binding were extracted from the genes that were suggested to be related to social behavior. These results suggest that DNA methylation contributes to the improvement of social deficits in ASD.

Academic Significance and Societal Importance of the Research Achievements

自閉症の主な症状は、社会性相互交流の障害であり、ヒトとのコミュニケーションや対人相互関係に困難を有するが、根本的な治療法は開発されていない。本研究は野生型マウスとペア飼育することによって、Tsc1+/-マウスの社会性行動障害が改善することを示した。さらに、ペア飼育によってDNAメチル化状態が変化することが見出された。これらのことから自閉症の社会性行動障害の改善にDNAメチル化が寄与することが示唆された。将来的に薬剤との相加・相乗効果を調べることで、標的となる遺伝子が明確になり、より効果的な治療法の開発につながることが期待される。

Research Products

• [Journal Article] Increased production of inflammatory cytokines and activation of microglia in the fetal brain of preeclamptic mice induced by angiotensin II (2022)
  • Author(s): 1)Katoh Y, Iriyama T, Yano E, Sayama S, Seyama T, Kotajima-Murakami H, Sato A, Sakuma H, Iguchi Y, Yoshikawa M, Inaoka N, Ichinose M, Toshimitsu M, Sone K, Kumasawa K, Nagamatsu T, Ikeda K, Osuga Y
  • Journal Title: J Reprod Immunol. Volume: 154 Pages: 103752-103752
  • DOI: 10.1016/j.jri.2022.103752
  • Peer Reviewed
• [Journal Article] Interaction between social behavior and paternal age in offspring of the same paternal mice (2022)
  • Author(s): Tanaka Miho、Sato Atsushi、Kotajima‐Murakami Hiroko、Kashii Hirofumi、Hagino Yoko、Ide Soichiro、Ikeda Kazutaka
  • Journal Title: Neuropsychopharmacology Reports Volume: 42 Issue: 3 Pages: 343-346
  • DOI: 10.1002/npr2.12258
  • Peer Reviewed / Open Access
• [Journal Article] Influence of Prenatal Drug Exposure, Maternal Inflammation, and Parental Aging on the Development of Autism Spectrum Disorder (2022)
  • Author(s): Sato A, Kotajima-Murakami H, Tanaka M, Katoh Y, Ikeda K
  • Journal Title: Front Psychiatry Volume: 13 Pages: 821455-821455
  • DOI: 10.3389/fpsyt.2022.821455
  • Peer Reviewed / Open Access
• [Journal Article] Exposure to GABAA Receptor Antagonist Picrotoxin in Pregnant Mice Causes Autism-Like Behaviors and Aberrant Gene Expression in Offspring (2022)
  • Author(s): Kotajima-Murakami H, Hagihara H, Sato A, Hagino Y, Tanaka M, Katoh Y, Nishito Y, Takamatsu Y, Uchino S, Miyakawa T, Ikeda K
  • Journal Title: Front Psychiatry Volume: 13 Pages: 821354-821354
  • DOI: 10.3389/fpsyt.2022.821354
  • Peer Reviewed / Open Access
• [Presentation] 結節性硬化症に伴う自閉スペクトラム症への行動療法による効果とメカニズムの解明. (2022)
  • Author(s): 古田島(村上)浩子
  • Organizer: 第10回日本結節性硬化症学会
  • Invited
• [Presentation] Exposure to GABAA receptor antagonist picrotoxin in pregnant mice causes autism-like behaviors and aberrant gene expression in offspring (2022)
  • Author(s): Hiroko Kotajima-Murakami
  • Organizer: NEURO2022
• [Presentation] Prenatal exposure of GABAA receptor inhibitor picrotoxin causes ASD-like behaviors and aberrant gene expression in mice. (2021)
  • Author(s): Kotajima-Murakami H, Sato A, Hagino Y, Tanaka M, Kato Y, Takamatsu Y, Nishito Y, Uchino S, Ikeda K
  • Organizer: 7th Congress of AsCNP
  • Int'l Joint Research
• [Presentation] mTORシグナル経路を中心とした自閉スペクトラム症の病態解明と治療法開発に向けて. (2021)
  • Author(s): 古田島浩子, 佐藤敦志, 池田和隆
  • 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] Exposure of picrotoxin, a GABAA receptor antagonist, in pregnant mice causes ASD-like behaviors in offspring. (2021)
  • Author(s): Kotajima H, Sato A, Hagino Y, Tanaka M, Kato Y, Takamatsu Y, Uchino S, Ikeda K
  • Organizer: CINP 2021 Virtual World Congress
  • Int'l Joint Research
• [Presentation] Exposure of Picrotoxin, a GABAA Receptor Antagonist, in Pregnant Mice Causes ASD-Like Behaviors in Offspring. (2020)
  • Author(s): Kotajima H, Sato A, Hagino Y, Tanaka M, Kato Y, Takamatsu Y, Uchino S, Ikeda K
  • Organizer: 59th Annual Meeting of The American College of Neuropsychopharmacology (ACNP 2020)
  • Int'l Joint Research
• [Presentation] 妊娠マウスへのGABA受容体阻害剤曝露による仔への影響 (2020)
  • Author(s): 古田島浩子, 佐藤敦志, 萩野洋子, 田中美歩, 加藤喜久, 高松幸雄, 内野茂夫, 池田和隆
  • Organizer: NPBPP2020
• [Presentation] Effects of rapamycin on social interaction deficits and gene expression in mice exposed to valproic acid in utero (2020)
  • Author(s): Hiroko KOTAJIMA-MURAKAMI
  • Organizer: 第2回脳科学サロン
• [Presentation] Exposure of GABA receptor inhibitor picrotoxin in pregnant mice causes ASD-like behaviors in offspring. (2020)
  • Author(s): Kotajima H, Sato A, Hagino Y, Tanaka M, Kato Y, Takamatsu Y, Uchino S, Ikeda K
  • Organizer: 第43回日本神経科学大会
• [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 (AsCNP2019)
  • 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 (AsCNP2019)
  • 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
• [Remarks] 依存性物質プロジェクト
  • URL: https://www.igakuken.or.jp/abuse/works_molecpsy/works2022.html#original