Regulation of synapse formation, maintenance, elimination and plasticity by C1q family proteins

• Project/Area Number: 15H05772
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Neurophysiology / General neuroscience
• Research Institution: Keio University
• Principal Investigator: YUZAKI Michisuke 慶應義塾大学, 医学部(信濃町), 教授 (40365226)
• Co-Investigator(Kenkyū-buntansha): 武内 恒成 愛知医科大学, 医学部, 教授 (90206946)
• Project Period (FY): 2015-05-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥176,540,000 (Direct Cost: ¥135,800,000、Indirect Cost: ¥40,740,000); Fiscal Year 2019: ¥34,190,000 (Direct Cost: ¥26,300,000、Indirect Cost: ¥7,890,000); Fiscal Year 2018: ¥33,670,000 (Direct Cost: ¥25,900,000、Indirect Cost: ¥7,770,000); Fiscal Year 2017: ¥33,670,000 (Direct Cost: ¥25,900,000、Indirect Cost: ¥7,770,000); Fiscal Year 2016: ¥35,100,000 (Direct Cost: ¥27,000,000、Indirect Cost: ¥8,100,000); Fiscal Year 2015: ¥39,910,000 (Direct Cost: ¥30,700,000、Indirect Cost: ¥9,210,000)
• Keywords: ニューロン / シナプス / 神経回路 / グルタミン酸受容体 / 補体

Outline of Final Research Achievements

Abnormal synaptic connections contribute to various neuropsychiatric, neurodevelopmental and neurological disorders, such as autism spectrum disorders, schizophrenia and Alzheimer’s dementia. However, it has remained largely unclear how vast numbers of connections are precisely established, maintained, and modified throughout life. In this study, we addressed this question by focusing on a new class of synaptic organizers, C1q family proteins. We have demonstrated how Cbln1, C11L1-3 proteins are released and functions in representative neural circuits of the hippocampus and the cerebellum.

Academic Significance and Societal Importance of the Research Achievements

精神・神経疾患において、脳領域間をつなぐシナプス結合に異常があることが近年明らかになってきた。本研究では、私たちが発見した補体ファミリー分子に焦点をあてて、この問いに挑んだ。近年、てんかんに伴って補体ファミリー分子Cbln1の発現が低下することによって自閉症を示すことが報告された。また、補体ファミリー分子の結晶構造に基づいて新たに開発した人工シナプスコネクターを投与すると、小脳失調やアルツハイマー病モデルマウスの症状を大幅に寛解させることもわかってきた。このように、シナプス形成分子の基礎的知見は発達障害や精神・神経疾患の病態や新しい治療法の開発に繋がることが期待される。

Assessment Rating

Verification Result (Rating)

A

Research Products

• [Int'l Joint Research] MRC-LMB（分子生物学研究所）(英国)
• [Int'l Joint Research] DZNE (ドイツ神経変性疾患センター）(ドイツ)
• [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] PIP3-Phldb2 is crucial for LTP regulating synaptic NMDA and AMPA receptor density and PSD95 turnover (2019)
  • Author(s): Xie Min-Jue、Ishikawa Yasuyuki、Yagi Hideshi、Iguchi Tokuichi、Oka Yuichiro、Kuroda Kazuki、Iwata Keiko、Kiyonari Hiroshi、Matsuda Shinji、Matsuzaki Hideo、Yuzaki Michisuke、Fukazawa Yugo、Sato Makoto
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 4305-4305
  • DOI: 10.1038/s41598-019-40838-6
  • Peer Reviewed / Open Access
• [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: in press
  • Peer Reviewed
• [Journal Article] Improvement of cerebellar ataxic gait by injecting Cbln1 into the cerebellum of cbln1-null mice (2018)
  • Author(s): E. Takeuchi，A. Ito-Ishida，M. Yuzaki，D. Yanagihara
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 6184-6184
  • DOI: 10.1038/s41598-018-24490-0
  • Peer Reviewed / Open Access
• [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] 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] Interneuronal NMDA receptors regulate long-term depression and motor learning in the cerebellum (2018)
  • Author(s): Kono Maya、Kakegawa Wataru、Yoshida Kazunari、Yuzaki Michisuke
  • Journal Title: The Journal of Physiology Volume: 597 Issue: 3 Pages: 903-920
  • DOI: 10.1113/jp276794
  • Peer Reviewed
• [Journal Article] Two classes of secreted synaptic organizers in the central nervous system (2018)
  • Author(s): Yuzaki M
  • Journal Title: Annu Rev Physiol Volume: 80 Issue: 1 Pages: 243-262
  • DOI: 10.1146/annurev-physiol-021317-121322
  • Peer Reviewed
• [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] The C1q complement family of synaptic organizers: not just complementary (2017)
  • Author(s): Michisuke Yuzaki
  • Journal Title: Current Opinion in Neurobioilogy Volume: 45 Pages: 9-15
  • DOI: 10.1016/j.conb.2017.02.002
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A GluD Coming-Of-Age Story (2017)
  • Author(s): Yuzaki M, Aricescu AR
  • Journal Title: Trends in Neuroscience Volume: 40 Issue: 3 Pages: 138-150
  • DOI: 10.1016/j.tins.2016.12.004
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [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
• [Journal Article] Computational Model of the GluA2-Y876/GluA2-S880 Master Switch for Cerebellar Long-Term Depression (2016)
  • Author(s): Gallimore AR, Aricescu AR, Yuzaki M, Calinescu R.A
  • Journal Title: PLOS Computational Biology Volume: 1004664
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel non-canonical Notch signaling regulates expression of synaptic vesicle proteins in excitatory neurons (2016)
  • Author(s): Hayashi Y, Nishimune H, Hozumi K, Saga Y, Harada A, Yuzaki M, Iwatsubo T, Kopan R, Tomita T.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 23969-23969
  • DOI: 10.1038/srep23969
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Controlling the Regional Identity of hPSC-Derived Neurons to Uncover Neuronal Subtype Specificity of Neurological Disease Phenotypes (2015)
  • Author(s): Imaizumi K, Sone T, Ibata K, Fujimori K, Yuzaki M, Akamatsu W, Okano H.
  • Journal Title: Stem Cell Reports Volume: Volume 5, Issue 6, Pages: 1010-1022
  • Peer Reviewed / Open Access
• [Journal Article] Anterograde C1ql1 signaling is required in order to determine and maintain a single-winner climbing fiber in the mouse cerebellum. (2015)
  • Author(s): Kakegawa W, Mitakidis N, Miura E, Abe M, Matsuda K, Takeo YH, Kohda K, Motohashi J, Takahashi A, Nagao S, Muramatsu SI, Watanabe M, Sakimura K, Aricescu AR, Yuzaki M.
  • Journal Title: Neuron Volume: Volume 85, Issue 2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Casting new light on synaptic plasticity using optogenetic tools (2019)
  • Author(s): 柚崎通介
  • Organizer: US-Japan Brain Research Cooperation Program
  • Int'l Joint Research / Invited
• [Presentation] New tools to modify functional & structural synaptic connectivity (2019)
  • Author(s): 柚崎通介
  • Organizer: UK-DRI Synapse Symposium
  • Int'l Joint Research / Invited
• [Presentation] Regulation of iGluRs by Extracellular Scaffolding Proteins (2019)
  • Author(s): 柚崎通介
  • Organizer: Gordon Research Conference
  • Int'l Joint Research / Invited
• [Presentation] Synaptic iGluRs: a privilege to be at synapses (2019)
  • Author(s): 柚崎通介
  • Organizer: Jacques Monod Conference
  • Int'l Joint Research / Invited
• [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 Federation of the Asian and Oceanian Physiological Societies (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
  • 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] ew 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] 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] The C1q complement family proteins and glutamate receptors: bridge over the synaptic cleft (2018)
  • Author(s): Matsuda Keiko, Yuzaki Michisuke
  • Organizer: 第95回日本生理学会大会
  • 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: ケントリッチ（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] Transsynaptic modulation of postsynaptic receptors by the C1q complement family (2016)
  • Author(s): Michisuke Yuzaki
  • Organizer: The US-Japan Brain Research Cooperative Program: Current Trends and Future Directions of Synaptic Plasticity Research
  • Place of Presentation: ボルチモア（アメリカ）
  • Year and Date: 2016-06-22
  • Int'l Joint Research / Invited
• [Presentation] 苔状線維が放出するC1qタンパク質による苔状線維－CA3シナプス機能の制御 Feed-forward modulation of hippocampal mossy fiber-CA3 synaptic functions by C1q proteins (2016)
  • Author(s): 松田 恵子 ,Timotheus Budisantoso、渡辺 雅彦,﨑村健司,A. Radu Aricescu,柚﨑 通介
  • Organizer: 第93回日本生理学会大会、フランス神経科学学会合同シンポジウム
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-03-23
  • 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
• [Presentation] 小脳プルキンエ細胞樹状突起発達におけるRORαの役割 Multiple roles of RORα in dendritic development of cerebellar Purkinje cells in vivo (2015)
  • Author(s): 竹尾 ゆかり, 掛川 渉, 三浦 会里子, 柚﨑 通介
  • Organizer: 第３８回日本神経科学大会
  • Place of Presentation: 神戸国際会議場、神戸国際展示場（兵庫県神戸市）
  • Year and Date: 2015-07-28
  • Int'l Joint Research / Invited
• [Presentation] 神経細胞内在性AMPARのライブイメージングを指向したケミカルラベル化法の開発 A novel chemical labeling technique for visualizing endogenous AMPA receptors in live neurons (2015)
  • Author(s): 若山 翔, 清中 茂樹 , 柚﨑 通介, 浜地 格
  • Organizer: 第３８回日本神経科学大会
  • Place of Presentation: 神戸国際会議場、神戸国際展示場（兵庫県神戸市）
  • Year and Date: 2015-07-28
  • Int'l Joint Research / Invited
• [Presentation] 新規の人工的シナプス接続分子、Cerebellin-Pentraxin（CPTX）を用いたシナプス形成および可塑性の制御 Modulation of synapse formation and plasticity by a novel artificial synapse connector, Cerebellin-Pentraxin (CPTX) (2015)
  • Author(s): 鈴木 邦道, 柚﨑 通介
  • Organizer: 第３８回日本神経科学大会
  • Place of Presentation: 神戸国際会議場、神戸国際展示場（兵庫県神戸市）
  • Year and Date: 2015-07-28
  • 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
• [Book] 「補体C1qファミリー分子」とシナプス形成・維持 (2016)
  • Author(s): 掛川渉、松田恵子、柚﨑通介
  • Total Pages: 276
  • Publisher: Annual Review 神経 2016
• [Book] 強きを助け弱きをくじく」－シナプス刈り込みを担う新規C1ql1シグナリング (2015)
  • Author(s): 掛川渉、柚﨑通介
  • Total Pages: 139
  • Publisher: 実験医学
• [Book] C1ql1：脳内シナプスの形態と機能を制御する新しい分子 (2015)
  • Author(s): 掛川渉、柚﨑通介
  • Total Pages: 114
  • Publisher: 細胞工学
• [Book] Purkinje細胞の樹状突起形成機構－新しい方法で古い転写因子RORαの役割解明に挑む (2015)
  • Author(s): 竹尾ゆかり、柚﨑通介
  • Total Pages: 100
  • Publisher: 医学のあゆみ
• [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/
• [Remarks] 慶應義塾大学医学部生理学柚崎研究室ＨＰ
  • URL: http://www.yuzaki-lab.org/
• [Patent(Industrial Property Rights)] 人工興奮性シナプスコネクタとその脊髄損傷処置への使用 (2020)
  • Inventor(s): 柚崎通介
  • Industrial Property Rights Holder: 慶應義塾
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-002879
  • Filing Date: 2020