Epigenetic mechanisms in schizophrenia by immune activation during pregnancy

• Project/Area Number: 16K07210
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical genome science
• Research Institution: Tohoku University
• Principal Investigator: YU ZHIQIAN 東北大学, 災害科学国際研究所, 助教 (60451639)
• Research Collaborator: TOMITA HIROAKI ; NAGASAKI MASAO ; NAKAYAMA KEIKO ; HASHIMOTO KENJI ; IWAMOTO KAZUYA ; KINOSHITA KENGO
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 統合失調症 / 遺伝子発現 / メチル化 / 環境要因 / 性差 / エピゲノム / 遺伝子 / Poly I:C / DNAメチル化 / 死後脳

Outline of Final Research Achievements

Gender differences in susceptibility to schizophrenia have been a hotly debated research issue for decades. Epidemiological evidence has shown that female offspring exposed to maternal infection during pregnancy are significantly more susceptible to developing schizophrenia. From an analysis of the offspring of poly I:C-treated pregnant mice we show that only female offspring of poly I:C-treated dams express schizophrenia-linked behavioral changes, profound genome-wide DNA hypermethylation profiles in the prefrontal cortices and postmortem prefrontal cortices of female patients with schizophrenia.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、脳発達や中枢神経系恒常性を維持するDNAメチル化機能、および環境要因によるメチル化の再編を明らかにし、統合失調症の発症メカニズムの解明に寄与する。また，マウスの雌雄差を解析することで, ヒトの男女間における脳の発達、特にDNAメチル化制御の違いを解明するための新しい戦略につながり、これらの知見により統合失調症を始めとする種々の精神疾患の発症機序の解明、および有効な治療薬の開発が進むことが期待される。

Research Products

• [Journal Article] Effect of the interaction between BDNF Val66Met polymorphism and daily physical activity on mean diffusivity (2019)
  • Author(s): Takeuchi Hikaru、Tomita Hiroaki、Taki Yasuyuki、Kikuchi Yoshie、Ono Chiaki、Yu Zhiqian、Sekiguchi Atsushi、Nouchi Rui、Kotozaki Yuka、Nakagawa Seishu、Miyauchi Carlos Makoto、Iizuka Kunio、Yokoyama Ryoichi、Shinada Takamitsu、Yamamoto Yuki、Hanawa Sugiko、Araki Tsuyoshi、Kunitoki Keiko、Sassa Yuko、Kawashima Ryuta
  • Journal Title: Brain Imaging and Behavior Volume: 該当なし Issue: 3 Pages: 806-820
  • DOI: 10.1007/s11682-018-0025-8
  • Peer Reviewed
• [Journal Article] A common CACNA1C gene risk variant has sex-dependent effects on behavioral traits and brain functional activity (2018)
  • Author(s): Takeuchi Hikaru、Tomita Hiroaki、Taki Yasuyuki、Kikuchi Yoshie、Ono Chiaki、Yu Zhiqian、Sekiguchi Atsushi、Nouchi Rui、Kotozaki Yuka、Nakagawa Seishu、Miyauchi Carlos Makoto、Iizuka Kunio、Yokoyama Ryoichi、Shinada Takamitsu、Yamamoto Yuki、Hanawa Sugiko、Araki Tsuyoshi、Kunitoki Keiko、Sassa Yuko、Kawashima Ryuta
  • Journal Title: Cereb Cortex Volume: 該当なし Issue: 8 Pages: 3211-3219
  • DOI: 10.1093/cercor/bhy189
  • Peer Reviewed
• [Journal Article] Polymorphisms in the microglial marker molecule CX3CR1 affect the blood volume of the human brain (2018)
  • Author(s): Sakai Mai、Takeuchi Hikaru、Yu Zhiqian、Kikuchi Yoshie、Ono Chiaki、Takahashi Yuta、Ito Fumiaki、Matsuoka Hiroo、Tanabe Osamu、Yasuda Jun、Taki Yasuyuki、Kawashima Ryuta、Tomita Hiroaki
  • Journal Title: Psychiatry and Clinical Neurosciences Volume: 72 Issue: 6 Pages: 409-422
  • DOI: 10.1111/pcn.12649
  • Peer Reviewed
• [Journal Article] Effect of tsunami drill experience on evacuation behavior after the onset of the Great East Japan Earthquake (2018)
  • Author(s): Nakaya Naoki、Nemoto Harumi、Yi Carine、Sato Ayako、Shingu Kotomi、Shoji Tomoka、Sato Shosuke、Tsuchiya Naho、Nakamura Tomohiro、Narita Akira、Kogure Mana、Sugawara Yumi、Yu Zhiqian、Gunawansa Nicole、Kuriyama Shinichi、Murao Osamu、Sato Takeshi、Imamura Fumihiko、Tsuji Ichiro、Hozawa Atsushi、Tomita Hiroaki
  • Journal Title: International Journal of Disaster Risk Reduction Volume: 28 Pages: 206-213
  • DOI: 10.1016/j.ijdrr.2018.02.037
  • Peer Reviewed
• [Presentation] Maternal infection alters methylome of schizophrenia loci in female brain (2018)
  • Author(s): Yu Z, Ueno K, Funayama R, Sakai M, Ono C, Nakayama K, Nakasaki S, Tomita H
  • Organizer: Society for Neuroscience 48th Annual Meeting
  • Int'l Joint Research
• [Presentation] Gender-specific gene expression profiling of the prefrontal cortices of social defeat stress model mice (2018)
  • Author(s): Sakai M, Yu Z, Ono C, Tomita H
  • Organizer: Society for Neuroscience 48th Annual Meeting
  • Int'l Joint Research
• [Presentation] 脳内炎症のPTSDとうつ病病態への関与 (2018)
  • Author(s): 兪 志前
  • Organizer: 医療心理懇話会第3回集会
  • Invited
• [Presentation] 胎生期免疫ストレスがエピベノムを介して精神行動に及ぼす影響の特定 (2018)
  • Author(s): 兪 志前, 小野 千晶, 富田 博秋
  • Organizer: 第63回日本人類遺伝子学会
• [Presentation] 反復社会挫折ストレスにおける前頭前皮質遺伝子発現の検討 (2018)
  • Author(s): 兪 志前, 坂井 舞，小野 千晶，富田 博秋
  • Organizer: 第40回日本生物学的精神医学会
• [Presentation] Molecular profile of female brain relevant to susceptibility to schizophrenia due to maternal infection (2018)
  • Author(s): Yu Z, Ueno K, Funayama R, Sakai M, Ono C, Nakayama K, Nakasaki S, Tomita H
  • Organizer: 第41回日本神経科学大会
• [Presentation] Immune activation during pregnancy in mice Leads different DNA methylation and gene expression between male and female offspring (2017)
  • Author(s): Zhiqian Yu, Ryo Funayama, Mai Sakai, Yoshie Kikuchi, Kenji Hashimoto, Masao Nagasaki, Keiko Nakayama, Hiroaki Tomita
  • Organizer: 第40回日本神経科学大会