Dynamic regulation of cerebellar neural circuits by "scrap and build" mechanisms

• Project Area: Dynamic regulation of brain function by Scrap & Build system
• Project/Area Number: 16H06461
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Keio University
• Principal Investigator: 柚崎 通介 慶應義塾大学, 医学部(信濃町), 教授 (40365226)
• Co-Investigator(Kenkyū-buntansha): 溝口 明 三重大学, 医学系研究科, 産学官連携講座教授 (90181916)
• Project Period (FY): 2016-06-30 – 2021-03-31
• Project Status: Discontinued (Fiscal Year 2020)
• Budget Amount: ¥98,930,000 (Direct Cost: ¥76,100,000、Indirect Cost: ¥22,830,000); Fiscal Year 2020: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2019: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2018: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2017: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2016: ¥21,970,000 (Direct Cost: ¥16,900,000、Indirect Cost: ¥5,070,000)
• Keywords: 神経科学 / 小脳 / シナプス / 樹状突起 / 発生・分化

Outline of Annual Research Achievements

小脳神経回路においては、発達期から成熟後にかけてさまざまな破壊を伴う創造現象（スクラップ＆ビルド）が観察される。まず、幼若プルキンエ細胞の複数の樹状突起は、生後8日目までに1本のみが選択的に強化されて残りは刈り込まれる。これまでに2光子顕微鏡を用いてin vivo小脳において樹状突起の選択的強化と除去を担う分子基盤の解明を進めた。プルキンエ細胞に発現するNMDA受容体の機能はこれまで謎であったが、細胞内Ca上昇とCaMKII活性化を介して、複数の樹状突起を1本化させることが判明した。また生後8日目以降になり、プルキンエ細胞に入力する複数の登上線維が刈り込まれて、1本の登上線維が選択的に強化される。この過程には登上線維が分泌するC1qL1とその受容体であるBai3が必須であることは知られていたが、成熟後にC1qL1-Bai3シグナリングが果たす役割は不明であった。これまでに成熟後にBai3が過剰活性化されると再び複数の登上線維がプルキンエ細胞を支配することを発見した。このような現象は、他の動物種や脳領域においてもさまざまな発達時期において起きることが知られている。これらの他の類似現象との比較を通して、「創造と破壊」が一体どのように連動するのか、発達期と成熟期でどのような原理が連続/非連続的に用いられるのか、といった問いに答えることによってスクラップ＆ビルド現象の基本原理の解明を目指した。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Visualization of AMPA receptors in living human brain with positron emission tomography. (2020)
  • Author(s): Miyazaki T, Nakajima W, Hatano M, Shibata Y, Kuroki Y, Arisawa T, Mimura M, Yuzaki M, Kato H, Higuchi M, Uchida H, Takahashi T.
  • Journal Title: Nature Medicine Volume: 26 Issue: 2 Pages: 281-288
  • DOI: 10.1038/s41591-019-0723-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors (2020)
  • Author(s): Luo, L.、19名略、Sinclair, J. L.、Stogsdill, J. A.、Traunmuller, L.、Wang, J.、Wortel, J.、 You, W.、 Abumaria, N.、 Beier, K. T.、 Brose, N.、 Burgess, H. A.、 Cepko, C. L.、 Cloutier, J. F.、 Eroglu, C.、 Goebbels, S.、 Kaeser, P. S.、 Kay, J. N.、 Lu, W.、 Luo, L.、 Mandai, K.、15名略、Kawabe, H.、 Craig, A. M.
  • Journal Title: Neuron Volume: 106 Issue: 1 Pages: 37-65
  • DOI: 10.1016/j.neuron.2020.01.008
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] In vivo two-photon imaging of anesthesia-specific alterations in microglial surveillance and photodamage-directed motility in mouse cortex (2019)
  • Author(s): Weilun Sun, Kunimichi Suzuki, Dmytro Toptunov, Stoyan Stoyanov, Michisuke Yuzaki, Leonard Khiroug and Alexander Dityatev
  • Journal Title: Frontier Neuroscience Volume: - Pages: 421-421
  • DOI: 10.3389/fnins.2019.00421
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activity-dependent secretion of synaptic organizer Cbln1 from lysosomes in granule cell axons (2019)
  • Author(s): Ibata K, Kono M, Narumi S, Motohashi J, Kakegawa W, Kohda K, Yuzaki M.
  • Journal Title: Neuron Volume: 102 Issue: 6 Pages: 1184-1198
  • DOI: 10.1016/j.neuron.2019.03.044
  • Peer Reviewed / Open Access
• [Journal Article] Mice lacking EFA6C/Psd2, a guanine nucleotide exchange factor for Arf6, exhibit lower Purkinje cell synaptic density but normal cerebellar motor functions. (2019)
  • Author(s): Saegusa S, Fukaya M, Kakegawa W, Tanaka M, Katsumata O, Sugawara T, Hara Y, Itakura M, Okubo T, Sato T, Yuzaki M, Sakagami H
  • Journal Title: PLoS One Volume: 14 Issue: 5 Pages: e0216960-e0216960
  • DOI: 10.1371/journal.pone.0216960
  • Peer Reviewed / Open Access
• [Journal Article] Hyaluronan synthesis supports glutamate transporter activity (2019)
  • Author(s): Hayashi MK, Nishioka T, Shimizu H, Takahashi K, Kakegawa W, Mikami T, Hirayama Y, Koizumi S, Yoshida S, Yuzaki M, Tammi M, Sekino Y, Kaibuchi K, Shigemoto-Mogami Y, Yasui M, Sato K.
  • Journal Title: Journal of Neurochemistry Volume: 150 Issue: 3 Pages: 249-263
  • DOI: 10.1111/jnc.14791
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activity-dependent secretion of synaptic organizer Cbln1 from lysosomes in granule cell axons. (2019)
  • Author(s): Ibata K, Kono M, Narumi S, Motohashi J, Kohda K, Yuzaki M.
  • Journal Title: Neuron Volume: -
  • Peer Reviewed
• [Journal Article] Optogenetic Control of Synaptic AMPA Receptor Endocytosis Reveals Roles of LTD in Motor Learning (2018)
  • Author(s): Kakegawa Wataru、Katoh Akira、Narumi Sakae、Miura Eriko、Motohashi Junko、Takahashi Akiyo、Kohda Kazuhisa、Fukazawa Yugo、Yuzaki Michisuke、Matsuda Shinji
  • Journal Title: Neuron Volume: 99 Issue: 5 Pages: 985-998
  • DOI: 10.1016/j.neuron.2018.07.034
  • Peer Reviewed / Open Access
• [Journal Article] Caveolin-1 Promotes Early Neuronal Maturation via Caveolae-Independent Trafficking of N-Cadherin and L1. (2018)
  • Author(s): Shikanai M, Nishimura YV, Sakurai M, Nabeshima YI, Yuzaki M, Kawauchi T.
  • Journal Title: iScience Volume: 7 Pages: 53-67
  • DOI: 10.1016/j.isci.2018.08.014
  • Peer Reviewed / Open Access
• [Journal Article] Cote JF. Spatiotemporal regulation of the GPCR activity of BAI3 by C1qL4 and Stabilin-2 controls myoblast fusion. (2018)
  • Author(s): Hamoud N, Tran V, Aimi T, Kakegawa W, Lahaie S, Thibault MP, Pelletier A, Wong GW, Kim IS, Kania A, Yuzaki M, Bouvier M,
  • Journal Title: Nat Commun Volume: 9 Issue: 1
  • DOI: 10.1038/s41467-018-06897-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glutamate transporter GLAST controls synaptic wrapping by Bergmann glia and ensures proper wiring of Purkinje cells (2017)
  • Author(s): Miyazaki T, Yamasaki M, Hashimoto K, Kohda K, Yuzaki M, Shimamoto K, Tanaka K, Kano M, Watanabe M.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114 Issue: 28 Pages: 7438
  • DOI: 10.1073/pnas.1617330114
  • URL: https://pure.teikyo.jp/en/publications/c25d18f5-49a3-45de-9d85-d01159c3a02e
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Functional interactions between transient receptor potential M8 and transient receptor potential V1 in the trigeminal system: Relevance to migraine pathophysiology (2017)
  • Author(s): Kayama Y, Shibata M, Takizawa T, Ibata K, Shimizu T, Ebine T, Toriumi H, Yuzaki M, Suzuki N.
  • Journal Title: Cephalalgia Volume: 38(5) Issue: 5 Pages: 833-845
  • DOI: 10.1177/0333102417712719
  • 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
• [Journal Article] Transsynaptic Modulation of Kainate Receptor Functions by C1q-like Proteins (2016)
  • Author(s): Matsuda K, Budisantoso T, Mitakidis N, Sugaya Y, Miura E, Kakegawa W, Yamasaki M, Konno K, Uchigashima M, Abe M, Watanabe I, Kano M, Watanabe M, Sakimura K, Aricescu AR, Yuzaki M.
  • Journal Title: Neuron Volume: 90 Issue: 4 Pages: 752
  • DOI: 10.1016/j.neuron.2016.04.001
  • URL: https://localhost/en/publications/d8d05ba5-11eb-4f5d-8f67-0eb097d2e36e
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Allosteric activation of membrane-bound glutamate receptors using coordination chemistry within living cells (2016)
  • Author(s): Shigeki Kiyonaka, Ryou Kubota, Yukiko Michibata, Masayoshi Sakakura, Hideo Takahashi, Tomohiro Numata, Ryuji Inoue, Michisuke Yuzaki, Itaru Hamachi
  • Journal Title: Nat. Chem. Volume: 8 Issue: 10 Pages: 958-967
  • DOI: 10.1038/nchem.2554
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Structural basis for integration of GluD receptors within synaptic organizer complexes. (2016)
  • Author(s): Elegheert, J., Kakegawa, W., Clay, E. J., Shanks, N., Behiels, E., Matsuda, K., Kohda, K., Miura, E., Rossmann, M., Mitakidis, N., Motohashi, J., Chang, T. V., Siebold, C., Greger, H. I., Nakagawa, T., K., Yuzaki, M., Aricescu, R.A.
  • Journal Title: Science Volume: 353 Issue: 6296 Pages: 295-299
  • DOI: 10.1126/science.aae0104
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Roles of Cbln1 in Non-Motor Functions of Mice (2016)
  • Author(s): Otsuka S, Konno K, Abe M, Motohashi J, Kohda K, Sakimura K, Watanabe M, Yuzaki M
  • Journal Title: Journal of Neuroscience Volume: 36 Issue: 46 Pages: 11801-11816
  • DOI: 10.1523/jneurosci.0322-16.2016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Casting new light on synaptic plasticity using optogenetic tools. (2019)
  • Author(s): Yuzaki M.
  • Organizer: Symposium on "Molecular Mechanisms of Glutamate Receptor Signaling"
  • Int'l Joint Research / Invited
• [Presentation] Bridge Over Troubled Synapses: A New Synthetic Synapse Organizer (2019)
  • Author(s): Yuzaki M.
  • Organizer: The Institut NeuroMyoGene (INMG) Seminar
  • Int'l Joint Research / Invited
• [Presentation] Synaptic iGluRs: a privilege to be at synapses. (2019)
  • Author(s): Yuzaki M.
  • Organizer: Jacques Monod Conference on "ligand-gated ion channels from atomic structure to synaptic transmission"
  • Int'l Joint Research / Invited
• [Presentation] Regulation of iGluRs by Extracellular Scaffolding Proteins (2019)
  • Author(s): Yuzaki M.
  • Organizer: Gordon Research Conference on Excitatory Synapses and Brain Function
  • Int'l Joint Research / Invited
• [Presentation] New tools to modify functional & structural synaptic connectivity (2019)
  • Author(s): Yuzaki M.
  • Organizer: UK-DRI Synapse Symposium on “Physiology and Pathophysiology in Synapse”
  • Int'l Joint Research / Invited
• [Presentation] Casting new light on synaptic plasticity using optogenetic tools (2019)
  • Author(s): Yuzaki M.
  • Organizer: US-Japan Brain Research Cooperation Program on “Current Trends and Future Directions of Synapse-Circuit Plasticity Research
  • Int'l Joint Research / Invited
• [Presentation] グルタミン酸受容体の人工的な活性制御を可能とする新規ケモジェネティクス法の開発 (2019)
  • Author(s): 小島憲人、掛川渉、道籏友紀子、窪田亮、柚崎通介、浜地格、清中茂樹
  • Organizer: 第92回日本生化学会大会
• [Presentation] Dynamic Roles of C1ql1-Bai3 Signaling in Formation and Elimination of Climbing Fibers in Adult Cerebellum (2019)
  • Author(s): Takahiro Aimi, Wataru Kakegawa and Michisuke Yuzaki
  • Organizer: Neuro2019
  • Int'l Joint Research
• [Presentation] Trans-synaptic control of iGluR localization and function through C1q families (2019)
  • Author(s): Keiko Matsuda, M. Abe, M. Watanabe, K. Sakimura, Michisuke Yuzaki
  • Organizer: CNRS - Jacques Monod conference
• [Presentation] Molecular Mechanisms Underlying Dynamic Changes of Synapses in Adult Cerebellum (2019)
  • Author(s): Takahiro Aimi, Wataru Kakegawa and Michisuke Yuzaki
  • Organizer: Current Trends and Future Directions of Synapse-Circuit Plasticity Research
• [Presentation] C1ql1-Bai3 Signaling Dynamically Modulates Climbing Fiber Synapses in Adult Cerebellum (2019)
  • Author(s): Takahiro Aimi, Wataru Kakegawa and Michisuke Yuzaki
  • Organizer: The 9th FAOPS Congress
  • Int'l Joint Research
• [Presentation] 補体ファミリーによるシナプス調節機構の解明に向けて (2018)
  • Author(s): 柚崎 通介
  • Organizer: 第41回日本神経科学大会シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] New Approaches to Old Problems: Towards Understanding Cerebellar LTD/LTP (2018)
  • Author(s): Michisuke Yuzaki
  • Organizer: The 75th Fujihara Seminar
  • Int'l Joint Research / Invited
• [Presentation] How to Scrap & Build Synapses: New Tools to Modify Function & Structure (2018)
  • Author(s): Michisuke Yuzaki
  • Organizer: Cold Spring Harbor Asia Conferences
  • Int'l Joint Research / Invited
• [Presentation] Where's the receptor?-Finding NMDA receptor responsible for cerebellar LTD (2018)
  • Author(s): Kono M., Kakegawa W., Yuzaki M.
  • Organizer: SRCA2018
  • Int'l Joint Research / Invited
• [Presentation] Bridge Over Troubled Synapses: Functional & Structural Insights. Symposium on the innovative progress of neuroscientific research through the use of advanced animal models. (2018)
  • Author(s): Michisuke Yuzaki
  • Organizer: Brain Research Institute,
  • Int'l Joint Research / Invited
• [Presentation] Bridge over troubled synapses: unexpected roles of complement proteins in the CNS (2017)
  • Author(s): Michisuke Yuzaki
  • Organizer: Keio-NUS symposium
  • Place of Presentation: ケントリッジ（シンガポール)
  • Year and Date: 2017-01-10
  • Int'l Joint Research / Invited
• [Presentation] Bridge Over Troubled Synapse: C1q Proteins, GluD Receptors, and Beyond. (2017)
  • Author(s): Michisuke Yuzaki
  • Organizer: Special Lecture, Society for Neuroscience,
  • Int'l Joint Research / Invited
• [Presentation] Transsynaptic modulation by extracellular protein scaffolds (ESPs). (2017)
  • Author(s): Michisuke Yuzaki
  • Organizer: The 40th Annual Meeting of the Japan Neuroscience Society,
  • Int'l Joint Research / Invited
• [Presentation] Expanding synaptic roles of the C1q complement family proteins. (2017)
  • Author(s): Michisuke Yuzaki
  • Organizer: Center for Functional Connectomics Seminar, (Korea Institute of Science and Technology)
  • Int'l Joint Research / Invited
• [Presentation] Exocytosis from lysosome-like organelle at synapses, (2017)
  • Author(s): Michisuke Yuzaki
  • Organizer: French-Japan Scientific Meeting on Neurobiology of Disease & Aging
  • Int'l Joint Research / Invited
• [Presentation] Bridge Over Troubled Synapses: Unexpected Roles of Complement Proteins in the CNS (2017)
  • Author(s): Michisuke Yuzaki
  • Organizer: NUS-Keio Joint Scientific Symposium on Frontiers of Translational Medicine.
  • Int'l Joint Research / Invited
• [Presentation] Bridge Over Troubled Synapses: Gaps Filled by C1q Proteins (2016)
  • Author(s): Michisuke Yuzaki
  • Organizer: JSPS Core-to-Core Program & OIST Joint Symposium “Nanoscopic Synaptic Function,”
  • Place of Presentation: Rizzan Sea-Park Hotel (沖縄県国頭郡恩納村)
  • Year and Date: 2016-09-25
  • Int'l Joint Research / Invited
• [Presentation] 補体ファミリー分子によるシナプス形成と除去機構 (2016)
  • Author(s): Michisuke Yuzaki
  • Organizer: 第３９回日本神経科学学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-07-20
  • Int'l Joint Research / Invited
• [Presentation] Synaptic Menage a Trois: A Bridge Over Troubled Synapses (2016)
  • Author(s): Michisuke Yuzaki
  • Organizer: 第47回生理研国際シンポジウム
  • Place of Presentation: Okazaki Conference Center (愛知県岡崎市)
  • Int'l Joint Research / Invited
• [Book] 老年精神医学雑誌 (2020)
  • Author(s): 柚崎通介
  • Total Pages: 110
  • Publisher: ワールドプランニング
• [Book] Clinical Neuroscience (2019)
  • Author(s): 掛川渉、松田信爾、柚崎通介
  • Total Pages: 148
  • Publisher: 中外医学社
• [Remarks] Yuzaki Lab
  • URL: http://www.yuzaki-lab.org/
• [Remarks] Yuzaki-Lab
  • URL: http://www.yuzaki-lab.org/
• [Remarks] 慶應義塾大学医学部生理学 柚﨑研究室
  • URL: http://www.yuzaki-lab.org/
• [Patent(Industrial Property Rights)] 人口興奮性シナプスコネクタとその脊髄損傷処置への使用 (2019)
  • Inventor(s): 柚崎通介,鈴木邦道
  • Industrial Property Rights Holder: 柚崎通介,鈴木邦道
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Acquisition Date: 2020