Molecular and cellular mechanisms of active zone structure and function by the CAST/ELKS protein family

• Project/Area Number: 15H04272
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: University of Yamanashi
• Principal Investigator: OHTSUKA Toshihisa 山梨大学, 大学院総合研究部, 教授 (40401806)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000); Fiscal Year 2017: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: 神経科学 / 神経伝達物質・受容体 / アクティブゾーン / 分子細胞神経科学 / 小脳 / CAST / ELKS

Outline of Final Research Achievements

In this project, we have attempted to uncover physiological roles of the presynaptic active zone proteins CAST and ELKS in basic neurotransmitter release, synaptic plasticity, and neural circuit formation. Then, we have demonstrated that CAST is involved in release probability of synaptic vesicle and its recycling with Rab6, and that SAD kinase-mediated phosphorylation of CAST controls active zone vesicle recycling for synaptic depression. CAST and ELKS ablation studies have also revealed that CAST regulates synaptic vesicle recycling and quantal size in the mouse hippocampus, the size and ribbon synapse formation in the retina, and neural circuit formation in the cerebellum.
These results suggest that the CAST/ELKS protein control not only basic neurotransmitter release but also synaptic reorganization in the brain.

Research Products

• [Journal Article] Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome (2018)
  • Author(s): Yabe I, Yaguchi H, Kato Y, Miki Y, Takahashi H, Tanikawa S, Shirai S, Takahashi I, Kimura M, Hama Y, Matsushima M, Fujioka S, Kano T, Watanabe M, Nakagawa S, Kunieda Y, Ikeda Y, Hasegawa M, Nishihara H, Ohtsuka T, Tanaka S, Tsuboi Y, Hatakeyama S, Wakabayashi K, Sasaki H
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 819-819
  • DOI: 10.1038/s41598-018-19198-0
  • NAID: 120006377499
  • Peer Reviewed / Open Access
• [Journal Article] Synaptic localisation of SRF coactivators, MKL1 and MKL2, and their role in dendritic spine morphology (2018)
  • Author(s): Kaneda Marisa、Sakagami Hiroyuki、Hida Yamato、Ohtsuka Toshihisa、Satou Natsumi、Ishibashi Yuta、Fukuchi Mamoru、Krysiak Anna、Ishikawa Mitsuru、Ihara Daisuke、Kalita Katarzyna、Tabuchi Akiko
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 727-727
  • DOI: 10.1038/s41598-017-18905-7
  • Peer Reviewed / Open Access
• [Journal Article] CAST: Its molecular structure and phosphorylation-dependent regulation of presynaptic plasticity (2018)
  • Author(s): Hamada Shun、Ohtsuka Toshihisa
  • Journal Title: Neurosci. Res. Volume: 127 Pages: 25-32
  • DOI: 10.1016/j.neures.2017.12.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Wnt5 Activity Asymmetry and Intercellular Signaling via PCP Proteins Polarize Node Cells for Left-Right Symmetry Breaking. (2017)
  • Author(s): Minegishi, K., Hashimoto, M., Ajima, R., Takaoka, K., Shinohara, K., Ikawa, Y., Nishimura, H., McMahon, AP., Willert, K., Okada, Y., Sasaki, H., Shi, D., Fujimori, T., Ohtsuka, T., Igarashi, Y., Yamaguchi, TP., Shimono, A., Shiratori, H., Hamada, H.
  • Journal Title: Dev Cell. Volume: 40 Issue: 5 Pages: 439-452
  • DOI: 10.1016/j.devcel.2017.02.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Auxiliary calcium channel subunitα2δ4 is required for axonal elaboration, synaptic transmission, and wiring of rod photoreceptors (2017)
  • Author(s): Wang, Y., Fehlhaber, K.E., Sarria, I., Cao, Y., Ingram, N.T., Guerrero-Given, D., Throesch, B., Baldwin, K., Kamasawa, N., Ohtsuka, T., Sampath, A.P., Martemyanov, K.A.
  • Journal Title: Neuron Volume: 93 Issue: 6 Pages: 1359-1374
  • DOI: 10.1016/j.neuron.2017.02.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SAD-B Phosphorylation of CAST Controls Active Zone Vesicle Recycling for Synaptic Depression. (2016)
  • Author(s): Mochida, S.*, Hida, Y., Tanifuji, S., Hagiwara, A., Hamada, S., Abe, M., Huan, M., Yasumura, M., Kitajima, I., Sakimura, K., Ohtsuka, T*.
  • Journal Title: Cell Reports Volume: 16 Issue: 11 Pages: 2901-2913
  • DOI: 10.1016/j.celrep.2016.08.020
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The active zone protein CAST regulates synaptic vesicle recycling and quantal size in the mouse hippocampus. (2016)
  • Author(s): Kobayashi S, Hida Y, Ishizaki H, Inoue E, Tanaka-Okamoto M, Yamasaki M, Miyazaki T, Masahiro F, Kitajima I, Takai Y, Watanabe M, Ohtsuka T, Manabe T
  • Journal Title: Eur J Neurosci. Volume: 44 Issue: 5 Pages: 2272-2284
  • DOI: 10.1111/ejn.13331
  • Peer Reviewed / Open Access
• [Journal Article] Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures. (2016)
  • Author(s): Uchigashima, M., Ohtsuka, T., Kobayashi, K., Watanabe, M.
  • Journal Title: PNAS Volume: - Issue: 15 Pages: 4206-4211
  • DOI: 10.1073/pnas.1514074113
  • NAID: 120005849913
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SAD-B Kinase regulates presynaptic vesicular dynamics at hippocampal Schaffer collateral synapses and affects contextual fear memory. (2016)
  • Author(s): Watabe, A.M., Nagase, M., Hagiwara, A., Hida, Y., Tsuji, M., Ochiai, T., Kato, F., Ohtsuka, T.
  • Journal Title: Journal of Neurochemistry Volume: 136: Issue: 1 Pages: 36-47
  • DOI: 10.1111/jnc.13379
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Integral system by the active zone proteins CAST and ELKS to control retinal synaptic transmission and photoreceptor remodeling. (2018)
  • Author(s): Ohtsuka T.
  • Organizer: 第95回日本生理学会大会
• [Presentation] Molecular Mechanisms of Presynaptic Transmission. (2018)
  • Author(s): Ohtsuka T.
  • Organizer: The first international symposium for frontend brain science: University of Yamanashi 2018.
  • Int'l Joint Research
• [Presentation] Integral system by CAST/ELKS protein family to regulate retinal photoreceptor development and maintenance. (2018)
  • Author(s): Ohtsuka T.
  • Organizer: BRI International Symposium 2018
  • Int'l Joint Research / Invited
• [Presentation] CAST Phosphorylation in Control of Short-term Plasticity at the presynaptic Active Zones. (2017)
  • Author(s): 大塚稔久
  • Organizer: 第40回日本神経科学大会
• [Presentation] Decoding short-term synaptic plasticity: implication of CAST phosphorylation in control of synaptic plasticity at the excitatory synapses (2016)
  • Author(s): Toshihisa Ohtsuka
  • Organizer: The 47th NIPS International Symposium “Decoding Synapses”
  • Place of Presentation: Okazaki Conference Center (OCC), Okazaki, Aichi
  • Year and Date: 2016-10-26
  • Int'l Joint Research / Invited
• [Presentation] Exploration of neural mechanism involved in the adequate (2016)
  • Author(s): Hagiwara A., Sugiyama N., Ohtsuka T.
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-07-20
• [Presentation] プレシナプス・キナーゼSAD-Bによるシナプス小胞ダイナミクスと可塑性制御の分子基盤 (2015)
  • Author(s): 大塚稔久
  • Organizer: 生理学研究所研究会「シナプス・神経ネットワークの機能ダイナミクス」
  • Place of Presentation: 生理学研究所（愛知県岡崎市）
  • Year and Date: 2015-12-03
  • Invited
• [Presentation] The active zone proteins CAST and ELKS regulate the structure and function of retinal ribbon synapses. (2015)
  • Author(s): Toshihisa Ohtsuka
  • Organizer: Ribbon Synapses Symposium
  • Place of Presentation: ゲッティンゲン（ドイツ）
  • Year and Date: 2015-09-24
  • Invited
• [Presentation] 神経終末アクティブゾーンの分子構造基盤とその破綻 ～構造分子解析から脳高次機能の解明へ向けて～ (2015)
  • Author(s): 大塚稔久
  • Organizer: 招待セミナー
  • Place of Presentation: 東京医科歯科大学（東京都文京区）
  • Year and Date: 2015-06-23
  • Invited
• [Presentation] CAST and ELKS: molecular determinants for the presynaptic active zone (2015)
  • Author(s): Toshihisa Ohtsuka
  • Organizer: Invited seminar
  • Place of Presentation: マイアミ(アメリカ合衆国）
  • Year and Date: 2015-06-03
  • Invited
• [Presentation] 神経伝達物質の放出から捉える脳の高次機能とその破綻 (2015)
  • Author(s): 大塚稔久
  • Organizer: 第10回山梨脳・血管セミナー
  • Place of Presentation: 甲府富士屋ホテル（山梨県甲府市）
  • Year and Date: 2015-04-24
  • Invited
• [Book] Presynaptic Terminals (2015)
  • Author(s): Ohtsuka, T.
  • Total Pages: 15
  • Publisher: Springer Japan
• [Remarks] 山梨大学医学部生化学講座第一教室ホームページ
  • URL: http://www.med.yamanashi.ac.jp/basic/bioche01/
• [Remarks] 山梨大学・大学院総合研究部・医学域基礎医学系・生化学講座第一教室
• [Remarks] 大塚研究室ホームページ
  • URL: http://www.med.yamanashi.ac.jp/basic/bioche01/index.html