Regulation of synapse plasticity by stimulation-dependent dephosphorylation and translocation of PSD-Zip70

• Project/Area Number: 18K06466
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Iwate Medical University
• Principal Investigator: Mayanagi Taira 岩手医科大学, 医歯薬総合研究所, 講師 (20432544)
• Co-Investigator(Kenkyū-buntansha): 祖父江 憲治 岩手医科大学, その他, 学長 (20112047) ; 木村 眞吾 岩手医科大学, 医学部, 准教授 (30214878)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: シナプス可塑性 / タンパク質局在変化 / リン酸化・脱リン酸化 / グルタミン酸 / PSD-Zip70 / シナプス応答 / 局在変化 / シナプス / 脱リン酸化 / リン酸化制御

Outline of Final Research Achievements

In response to glutamate stimulation, dephosphorylated PSD-Zip70 rapidly translocates from the postsynaptic site to endosomes via binding to lipid chaperon Unc119. The depletion of PSD-Zip70 at postsynaptic sites causes transient activation of Rap2, which impairs postsynaptic responsiveness via internalization of AMPA-type glutamate receptors. Deficiency of PSD-Zip70 in the hippocampus failed to induce long term depression, a form of activity-dependent synaptic plasticity. Further, PSD-Zip70-knockout mice exhibits defects in working memory and cognition as well as enhanced anxiety-like behaviors. These findings provide molecular foundation to elucidate the regulatory mechanism in stimulation-dependent synaptic plasticity concerning higher brain function such as memory and emotional control.

Academic Significance and Societal Importance of the Research Achievements

神経細胞はシナプスを介して他の神経細胞と回路を形成し、情報を伝達する。我々は神経細胞が神経伝達物質グルタミン酸の刺激を受けるとシナプスに存在しているPSD-Zip70タンパク質が速やかに働きを変化させ、シナプスの応答性を調節しているRap2タンパク質の機能を制御していることを明らかにした。マウスを用いた実験からPSD-Zip70はストレスによる神経機能の変化に関わっており、PSD-Zip70がないと短期記憶の障害、不安の増大が生じることも見い出している。今回明らかにしたシナプス伝達を制御する仕組みは記憶や感情の調節など脳の複雑な働きを理解する上で重要な知見となる。

Research Products

• [Journal Article] Social Stress-Induced Postsynaptic Hyporesponsiveness in Glutamatergic Synapses Is Mediated by PSD-Zip70-Rap2 Pathway and Relates to Anxiety-Like Behaviors (2020)
  • Author(s): Mayanagi Taira、Sobue Kenji
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 13 Pages: 564-564
  • DOI: 10.3389/fncel.2019.00564
  • Peer Reviewed / Open Access
• [Journal Article] Kensuke Asakura, Taira Mayanagi, Shingo Kimura, Tamotsu Sugai, Takayuki Matsumoto, Kenji Sobue. (2019)
  • Author(s): Kensuke Asakura, Taira Mayanagi, Shingo Kimura, Tamotsu Sugai, Takayuki Matsumoto, Kenji Sobue.
  • Journal Title: 岩手医学雑誌 Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Myocardin-related transcription factor A (MRTF-A) regulates TGF-β2-induced type I collagen production in human lens epithelial cells. (2018)
  • Author(s): Takashi Okuno , Toshiyasu Imaizumi, Umi Sakamoto, Daisuke Sakai, Kazuhiro Fukuda, Atsushi Sanbe, Taira Mayanagi, Kenji Sobue, Daijiro Kurosaka.
  • Journal Title: 岩手医学雑誌 Volume: 70 Pages: 81-90
  • NAID: 130007473038
  • Peer Reviewed / Open Access
• [Presentation] Involvement of Rap2-mediated prefrontal dysfunction in social stress-induced anxiety. (2018)
  • Author(s): 真柳 平、祖父江 憲治
  • Organizer: 第41回 日本神経科学大会
• [Presentation] 消化管平滑筋におけるh-Caldesmonの生理的役割の解明 (2018)
  • Author(s): 朝倉謙輔 、真柳平、木村眞吾、菅井有、祖父江憲治、松本主之
  • Organizer: 第56回小腸学会学術集会
• [Presentation] Possible role of h-caldesmon in the pathogenesis of gastrointestinal motility disorders (2018)
  • Author(s): Kensuke Asakura, Taira Mayanagi, Shingo Kimura, Tamotsu Sugai, Kenji Sobue, Takayuki Matsumoto
  • Organizer: GI Research
  • Int'l Joint Research
• [Presentation] ストレス起因性の不安におけるRap2活性化を伴う前頭前皮質の機能低下の関与 (2018)
  • Author(s): 真柳 平、祖父江 憲治
  • Organizer: 日本生化学会 東北支部 第84回 例会