The effect of extracellular Calcium dynamics on synaptic transmission

• Project/Area Number: 17K15562
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General physiology
• Research Institution: Keio University
• Principal Investigator: Arai Itaru 慶應義塾大学, 医学部(信濃町), 助教 (00754631)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 小脳 / 長期可塑性 / δ2型グルタミン酸受容体 / Dセリン / 細胞外Ca濃度 / シナプス可塑性 / 細胞外カルシウム / デルタ型グルタミン酸受容体 / 細胞外カルシウム濃度 / 平行線維シナプス / 記憶・学習 / シナプス伝達 / 細胞外Ca2+

Outline of Final Research Achievements

Delta2 glutamate receptors (GluD2), which express in cerebellar parallel fiber - Purkinje cell synapses and induce long term depression by binding with D-serine (D-LTD), have Ca2+ binding sites at their ligand binding domain. In this study, I investigated how D-LTD is influenced by the extracellular Ca2+ concentration([Ca]o) dynamics during synaptic activities.
When [Ca]o was reduced during the LTD induction, D-LTD was facilitated. On the other hand, D-LTD was inhibited when [Ca]o was elevated during its induction. Moreover, D-LTD was always facilitated when the similar experiments were performed by using knock in mice that have mutant GluD2 whose Ca2+ binding ability was disrupted. These results indicate that D-serine - GluD2 signaling is regulated by the [Ca]o dynamics during synaptic activities.

Academic Significance and Societal Importance of the Research Achievements

中枢神経系においてグルタミン酸によるシナプス伝達は神経活動依存的に様々な制御を受けて記憶・学習等の基盤となるが、その制御機構には未だ不明な点も多い。近年、グルタミン酸受容体の構造解析から細胞外領域にイオン結合部位が存在することが明らかになった。一方、シナプス近傍の細胞外イオン濃度は神経活動依存的に変化する。本研究は、小脳平行線維シナプスに局在するGluD2を用いて、細胞外イオン濃度の活動依存的変化がシナプス伝達を制御するという、これまで考えられてこなかった全く新しいシナプス制御機構の存在を示唆しており、得られた知見は他のグルタミン酸受容体を介したシナプス伝達の制御機構への応用も期待される。

Research Products

• [Journal Article] Chemical labelling for visualizing native AMPA receptors in live neurons. (2017)
  • Author(s): Wakayama, S., Kiyonaka, S., Arai, I., Kakegawa, W., Matsuda, S., Ibata, K., Nemoto, Y.L., Kusumi, A., Yuzaki, M., Hamachi, I.
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 14850-14850
  • DOI: 10.1038/ncomms14850
  • NAID: 120006600363
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neural differentiation of human embryonic stem cells induced by the transgene-mediated overexpression of single transcription factors (2017)
  • Author(s): Matsushita Misako、Nakatake Yuhki、Arai Itaru、Ibata Keiji、Kohda Kazuhisa、Goparaju Sravan K.、Murakami Miyako、Sakota Miki、Chikazawa-Nohtomi Nana、Ko Shigeru B.H.、Kanai Takanori、Yuzaki Michisuke、Ko Minoru S.H.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 490 Issue: 2 Pages: 296-301
  • DOI: 10.1016/j.bbrc.2017.06.039
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dendritic Homeostasis Disruption in a Novel Frontotemporal Dementia Mouse Model Expressing Cytoplasmic Fused in Sarcoma (2017)
  • Author(s): Shiihashi Gen、Ito Daisuke、Arai Itaru、Kobayashi Yuki、Hayashi Kanehiro、Otsuka Shintaro、Nakajima Kazunori、Yuzaki Michisuke、Itohara Shigeyoshi、Suzuki Norihiro
  • Journal Title: EBioMedicine Volume: 24 Pages: 102-115
  • DOI: 10.1016/j.ebiom.2017.09.005
  • Peer Reviewed / Open Access / Int'l Joint Research