Postsynaptic calcineurin regulates input-specific synapse formation

• Project/Area Number: 17K08485
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General anatomy (including histology/embryology)
• Research Institution: Hokkaido University
• Principal Investigator: Miyazaki Taisuke 北海道大学, 保健科学研究院, 准教授 (90374230)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: プルキンエ細胞 / カルシニューリン / GABA / シナプス特異性 / 抑制性シナプス / GABA受容体 / バスケット細胞 / カルシウム

Outline of Final Research Achievements

Cerebellar Purkinje cells form axo-spinous and axo-dendritic synapse with excitatory and inhibitory terminals, respectively. It has been unclear what mechanism regulates the input-specific synapse formation. To understand mechanism of the input-specific synapse formation, the present analysis focused on calcium-dependent phosphatase calcineurin, which regulates long-term synaptic transmission. By anatomical investigation, CNB1, a catalytic subunit of calcineurin expressed at Purkinje cells and molecular layer interneuron which send inhibitory input to Purkinje cells. Moreover, in Purkinje cell specific CNB1-deficient model mice, inhibitory terminals frequently contacted to excitatory Purkinje cell spines whose potsynapse expressed both excitatory and inhibitory neurotransmitter receptors. This result indicates that postsynaptic CNB1 regulates input-specific synapse formation in the developing cerebellum.

Academic Significance and Societal Importance of the Research Achievements

中枢神経系の多くは興奮性および抑制性ニューロンに大別され、それらの入力を受けるシナプス後部ではそれぞれの神経伝達物質に対応したシナプス形成様式と神経伝達物質受容体発現が見られる。このようなシナプス形成様式は神経終末依存的な分子機構があると考えられてきたが、その実態については不明な点が多く残されていた。本研究の結果から、長期シナプス伝達に関わることが知られているカルシニューリンがシナプス後部において入力特異的なシナプス形成様式に関わっていることが示唆された。この研究により得られた成果はこれまでのシナプス形成様式モデルとは一線を画し、今後の発展が期待される学術的意義の高いものであると考えられる

Research Products

• [Journal Article] Expression mapping, quantification, and complex formation of GluD1 and GluD2 glutamate receptors in adult mouse brain (2019)
  • Author(s): Nakamoto Chihiro、Konno Kohtarou、Miyazaki Taisuke、Nakatsukasa Ena、Natsume Rie、Abe Manabu、Kawamura Meiko、Fukazawa Yugo、Shigemoto Ryuichi、Yamasaki Miwako、Sakimura Kenji、Watanabe Masahiko
  • Journal Title: Journal of Comparative Neurology Volume: 528 Issue: 6 Pages: 1003-1027
  • DOI: 10.1002/cne.24792
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Elavl3 is essential for the maintenance of Purkinje neuron axons (2018)
  • Author(s): Ogawa Yuki、Kakumoto Kyoko、Yoshida Tetsu、Kuwako Ken-ichiro、Miyazaki Taisuke、Yamaguchi Junji、Konno Ayumu、Hata Junichi、Uchiyama Yasuo、Hirai Hirokazu、Watanabe Masahiko、Darnell Robert B.、Okano Hideyuki、Okano Hirotaka James
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 2722-2722
  • DOI: 10.1038/s41598-018-21130-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Maturation of Cerebellar Purkinje Cell Population Activity during Postnatal Refinement of Climbing Fiber Network. (2017)
  • Author(s): Good JM, Mahoney M, Miyazaki T, Tanaka KF, Sakimura K, Watanabe M, Kitamura K, Kano M.
  • Journal Title: Cell Rep. Volume: 21(8) Issue: 8 Pages: 2066-2073
  • DOI: 10.1016/j.celrep.2017.10.101
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Retrograde BDNF to TrkB signaling promotes synapse elimination in the developing cerebellum. (2017)
  • Author(s): Choo M, Miyazaki T, Yamazaki M, Kawamura M, Nakazawa T, Zhang J, Tanimura A, Uesaka N, Watanabe M, Sakimura K, Kano M.
  • Journal Title: Nat Commun. Volume: 8(1) Issue: 1 Pages: 195-195
  • DOI: 10.1038/s41467-017-00260-w
  • Peer Reviewed / Open Access
• [Journal Article] Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice. (2017)
  • Author(s): Nakai N, Nagano M, Saitow F, Watanabe Y, Kawamura Y, Kawamoto A, Tamada K, Mizuma H, Onoe H, Watanabe Y, Monai H, Hirase H, Nakatani J, Inagaki H, Kawada T, Miyazaki T, Watanabe M, Sato Y, Okabe S, Kitamura K, Kano M, Hashimoto K, Suzuki H, Takumi T.
  • Journal Title: Sci Adv. Volume: 3(6) Issue: 6
  • DOI: 10.1126/sciadv.1603001
  • Peer Reviewed / Open Access
• [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(28) Issue: 28 Pages: 7438-7443
  • DOI: 10.1073/pnas.1617330114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Alternative splicing in the C-terminal tail of Cav2.1 is essential for preventing a neurological disease in mice. (2017)
  • Author(s): Aikawa T, Watanabe T, Miyazaki T, Mikuni T, Wakamori M, Sakurai M, Aizawa H, Ishizu N, Watanabe M, Kano M, Mizusawa H, Watase K.
  • Journal Title: Hum Mol Genet. Volume: 26(16) Pages: 3094-3104
  • DOI: 10.1093/hmg/ddx193
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 小脳ルガロ細胞の帯状構造特異的な入出力様式 (2020)
  • Author(s): Taisuke Miyazaki, Miwako Yamasaki, Kenji F. Tanaka, Masahiko Watanabe
  • Organizer: 第125回日本解剖学会総会・全国学術集会
• [Presentation] 小脳ルガロ細胞の帯状構造特異的な入力様式と介在ニューロンへの抑制性支配様式 (2019)
  • Author(s): Taisuke Miyazaki, Miwako Yamasaki, Kenji F. Tanaka, Masahiko Watanabe
  • Organizer: Neuro2019
• [Presentation] Principal rule of neurotransmitter receptor localization at synapse (2019)
  • Author(s): Taisuke Miyazaki, Matthijs Verhage, Masahiko Watanabe, Susumu Tomita
  • Organizer: Current Trends and Future Directions of Synapse-Circuit Plasticity Research
  • Int'l Joint Research
• [Presentation] Morphological classification of cerebellar interneurons and their connections (2018)
  • Author(s): Taisuke Miyazaki, Miwako Yamasaki, Kenji F. Tanaka , Masahiko Watanabe
  • Organizer: Synaptic transmission Gordon Research Conference August 12-17, 2018 (Waterville Valley, NH)
  • Int'l Joint Research
• [Presentation] Calcineurin B1 subunit CNB1 in Purkinje cells regulates precise pre- and postsynaptic matching in inhibitory synapse formation (2018)
  • Author(s): Taisuke Miyazaki, Kenji Sakimura , Masahiko Watanabe
  • Organizer: 第８回新潟大学脳研究所共同研究拠点国際シンポジウム（新潟県新潟市）
  • Int'l Joint Research
• [Presentation] カルシウムチャネルCav2.1は成体期プルキンエ細胞の生存、バンド状発現、神経支配テリトリーの維持に不可欠である (2017)
  • Author(s): 宮崎 太輔, 山崎 美和子 ,崎村 建司, 渡辺 雅彦
  • Organizer: 第63回東北・北海道連合支部学術集会（青森県弘前市）
• [Presentation] プルキンエ細胞に発現するカルシニューリンB1サブユニットは抑制性シナプス形成過程において適切なプレ－ポストシナプスの接着に関わっている (2017)
  • Author(s): Taisuke Miyazaki, Kenji Sakimura , Masahiko Watanabe
  • Organizer: 第４０回日本神経科学大会（千葉県幕張市）