How synapses regulates neuronal wiring?: activity-dependent development of Cerebellar circuit

• Project/Area Number: 16K07001
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurophysiology / General neuroscience
• Research Institution: Keio University
• Principal Investigator: Takeo Yukari 慶應義塾大学, 医学部(信濃町), 特別研究員(PD) (90624320)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 神経細胞 / 樹状突起 / 発達 / 神経活動 / 小脳 / プルキンエ細胞 / 登上線維 / 平行線維 / 神経科学

Outline of Final Research Achievements

How neural circuit is formed precisely during development is unclear especially in mammalian brains. To understand the mechanism, we observed single neuron developing their dendritic morphology by in vivo two-photon imaging of murine cerebellar Purkinje cells. We found that immature Purkinje cells retract many immature dendrites before establish a single mature dendritic tree.Interestingly, this dendritic retraction required neural activities. Furthermore, we found that NMDAR and CaMK2 is required for this process, which is a an outstanding finding because it had been unclear if NMDAR had any roles in Purkinje cells despite the fact that NMDAR and CaMK2-dependent downstream signaling mechanisms play various important roles in other neuron types. Our findings suggest that dendritic morphology is regulated in an activity-dependent manner, and thus are highly intriguing in respect of mechanisms of circuit development as well as roles of immature neural activities.

Academic Significance and Societal Importance of the Research Achievements

神経細胞はシナプスによって神経回路内で情報を伝達する。神経回路は神経細胞の軸索と樹状突起がシナプス結合することで形成される。多くの神経細胞は胎児期から生後の早い時期にかけて神経回路を形成するが、回路形成中においてシナプスを介した情報伝達がどんな役割を持つのは不明であった。本研究ではマウスの小脳プルキンエ細胞を使って、成熟したシナプスにおいて脳機能に非常に大切であることが知られる、NMDA型グルタミン酸受容体が、発達中の樹状突起の形成に必要であることを発見した。この発見は、発達中のシナプスによる相互作用が回路形成を促すことを示す、脳の発達機構において重要な知見である。

Research Products

• [Journal Article] Cellular and Subcellular Localization of Endogenous Neuroligin-1 in the Cerebellum. (2018)
  • Author(s): Nozawa K, Hayashi A, Motohashi J, Takeo YH, Matsuda K, Yuzaki M.
  • Journal Title: Cerebellum Volume: 17 Issue: 6 Pages: 709-721
  • DOI: 10.1007/s12311-018-0966-x
  • Peer Reviewed
• [Journal Article] MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment. (2017)
  • Author(s): Satake T, Yamashita K, Hayashi K, Miyatake S, Tamura-Nakano M, Doi H, Furuta Y, Shioi G, Miura E, Takeo YH, Yoshida K, Yahikozawa H, Matsumoto N, Yuzaki M, Suzuki A.
  • Journal Title: EMBOJ Volume: 36 Issue: 9 Pages: 1227-1242
  • DOI: 10.15252/embj.201695630
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] In vivo dendritic development of cerebellar Purkinje cells (2017)
  • Author(s): Y. TAKEO, E. MIURA, M. YUZAKI
  • Organizer: Neuroscience 2017
  • Int'l Joint Research