Visualization of disrupted glutamate dynamics in the brain upon psychiatric disorders

• Project/Area Number: 16K08543
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: The University of Tokyo
• Principal Investigator: Okubo Yohei 東京大学, 大学院医学系研究科(医学部), 講師 (40422282)
• 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: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 統合失調症 / うつ / グルタミン酸 / 脳・神経 / 薬理学 / うつ病

Outline of Final Research Achievements

Although disruption of glutamate dynamics in the brain is atracting attention as a cause of psychiatric disorders, many points remain elusive. We thus set out to apply our unique glutamate fluorescence imaging technique for psychiatric disorders including schizophrenia and depression, and tried to clarify the disrupted glutamate dynamics and its mechanism in the brain. We for the first time found a spontaneous and spatially confined increase in glutamate concentration in the cerebral cortex. Since this glutamate dynamics was observed even under the inhibition of neuronal activity, release from glial cells, in particular astrocytes, was expected. It is expected to be a factor of non-neural factor for the disruption of glutamate dynamics in the pathological condition, and further analysis of the mechanism and elucidation of the causal relationship are awaited.

Academic Significance and Societal Importance of the Research Achievements

精神疾患のメカニズムは未だ不明な点が多く、既存の治療法は社会的要請を十分に満たしていない。本研究で発見されたグルタミン酸動態を評価軸にして病態や既存薬の効果を解析することで、治療抵抗性の統合失調症やうつ病に対する新たな治療法の開発に資する知見が得られることが期待される。

Research Products

• [Journal Article] Inositol 1,4,5-trisphosphate receptor type 2-independent Ca2+ release from the endoplasmic reticulum in astrocytes (2019)
  • Author(s): Okubo Yohei、Kanemaru Kazunori、Suzuki Junji、Kobayashi Kenta、Hirose Kenzo、Iino Masamitsu
  • Journal Title: Glia Volume: 67 Issue: 1 Pages: 113-124
  • DOI: 10.1002/glia.23531
  • NAID: 130007812856
  • Peer Reviewed
• [Journal Article] Visualization of astrocytic intracellular Ca2+ mobilization (2019)
  • Author(s): Okubo Yohei、Iino Masamitsu
  • Journal Title: The Journal of Physiology Volume: 印刷中 Issue: 9 Pages: 1671-1681
  • DOI: 10.1113/jp277609
  • Peer Reviewed / Open Access
• [Journal Article] Role of endoplasmic reticulum-mediated Ca2+ signaling in neuronal cell death (2018)
  • Author(s): Okubo Yohei、Mikami Yoshinori、Kanemaru Kazunori、Iino Masamitsu
  • Journal Title: Antioxid Redox Signal (in press) Volume: - Issue: 12 Pages: 1147-1157
  • DOI: 10.1089/ars.2018.7498
  • Peer Reviewed
• [Journal Article] Nitric Oxide-induced Activation of the Type 1 Ryanodine Receptor Is Critical for Epileptic Seizure-induced Neuronal Cell Death (2016)
  • Author(s): Mikami, Y., Kanemaru, K., Okubo, Y., Nakaune, T., Suzuki, J., Shibata, K., Sugiyama, H., Koyama, R., Murayama, T., Ito, A., Yamazawa, T., Ikegaya, Y., Sakurai, T., Saito, N., Kakizawa, S. and Iino, M.
  • Journal Title: EBioMedicine. Volume: 11 Pages: 253
  • DOI: 10.1016/j.ebiom.2016.08.020
  • URL: https://pure.teikyo.jp/en/publications/da2c0e23-a2fe-49e6-85de-a131287689de
  • Peer Reviewed / Open Access
• [Journal Article] Whisker experience-dependent mGluR signaling maintains synaptic strength in the mouse adolescent cortex. (2016)
  • Author(s): Kubota, J., Mikami, Y., Kanemaru, K., Sekiya, H., Okubo, Y. and Iino, M.
  • Journal Title: Eur. J. Neurosci. Volume: 44 Issue: 3 Pages: 2004-2014
  • DOI: 10.1111/ejn.13285
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] アストロサイトにおけるIP3受容体2型非依存性Ca2+放出 (2019)
  • Author(s): 大久保 洋平、金丸 和典、鈴木 純二、小林 憲太、廣瀬 謙造、飯野 正光
  • Organizer: 第92回 日本薬理学会年会
• [Presentation] Visualization of Ca2+ dynamics within the endoplasmic reticulum in neurons and glial cells (2019)
  • Author(s): Yohei Okubo
  • Organizer: 第22回 日韓薬理合同セミナー
  • Int'l Joint Research
• [Presentation] Visualization of Ca2+ dynamics within the endoplasmic reticulum for the study of astrocytic functions (2018)
  • Author(s): Yohei Okubo, Kazunori Kanemaru, Masamitsu Iino
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] アストロサイトにおけるIP3受容体2型非依存性Ca2+放出 (2018)
  • Author(s): 大久保 洋平、金丸 和典、廣瀬 謙造、飯野 正光
  • Organizer: 生理研研究会「シグナル動態の可視化と操作に基づく多階層機能解析の新展開」
• [Presentation] Visualization of metabotropic glutamate receptor signaling in neurons (2018)
  • Author(s): Yohei Okubo
  • Organizer: 次世代薬理学セミナー2018
  • Int'l Joint Research / Invited
• [Presentation] アストロサイト機能の解析に向けた小胞体内腔Ca2+動態可視化 (2017)
  • Author(s): 大久保 洋平、金丸 和典、飯野 正光
  • Organizer: 第90回 日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール（長崎県長崎市）
  • Year and Date: 2017-03-15
• [Presentation] Nitric oxide contributes to epileptic seizure-induced neuronal death (2017)
  • Author(s): Yohei Okubo
  • Organizer: 38th world congress of the international union of physiological sciences
  • Int'l Joint Research / Invited
• [Presentation] てんかん誘発性神経細胞死を担う一酸化窒素依存性1型リアノジン受容体活性化 (2017)
  • Author(s): 大久保 洋平、三上 義礼、金丸 和典、飯野 正光
  • Organizer: 生理研研究会「シグナル動態の可視化と操作に基づく多階層機能解析の新展開」
• [Presentation] Visualization of Ca2+ filling mechanisms upon synaptic inputs in the endoplasmic reticulum of cerebellar Purkinje cells (2017)
  • Author(s): Yohei Okubo, Junji Suzuki, Kazunori Kanemaru, Naotoshi Nakamura, Tatsuo Shibata, Masamitsu Iino
  • Organizer: 20th International Symposium on Calcium Binding Proteins and Calcium Function in Health and Disease
  • Int'l Joint Research
• [Presentation] 小胞体内腔Ca2+イメージングによる神経・グリア細胞機能の解析 (2017)
  • Author(s): 大久保 洋平
  • Organizer: 2017年度生命科学系学会合同年次大会
  • Invited
• [Presentation] 成熟マウス大脳皮質におけるmGluRを介した経験依存性シナプス維持機構 (2016)
  • Author(s): 大久保 洋平、久保田 淳、三上 義礼、金丸 和典、関谷 敬、飯野 正光
  • Organizer: 生理研研究会「生体シグナルダイナミクス研究会」
  • Place of Presentation: 生理学研究所（愛知県岡崎市）
  • Year and Date: 2016-09-15
• [Presentation] 成熟マウス大脳皮質におけるmGluRを介した経験依存性シナプス維持機構 (2016)
  • Author(s): 大久保 洋平、久保田 淳、三上 義礼、金丸 和典、関谷 敬、飯野 正光
  • Organizer: 第134回 日本薬理学会関東部会
  • Place of Presentation: 国際医療福祉大学（栃木県大田原市）
  • Year and Date: 2016-07-06
• [Remarks] 東京大学大学院医学系研究科細胞分子薬理学教室
  • URL: http://calcium.cmp.m.u-tokyo.ac.jp/
• [Remarks] 東京大学大学院医学系研究 科細胞分子薬理学教室
  • URL: http://calcium.cmp.m.u-tokyo.ac.jp/