シナプスにおける逆行性シグナルが生後発達期の機能的神経回路形成に果たす役割の解明

2018 Fiscal Year Annual Research Report

• Project/Area Number: 25000015
• Research Institution: The University of Tokyo
• Principal Investigator: 狩野 方伸 東京大学, 医学系研究科, 教授
• Project Period (FY): 2013 – 2018
• Keywords: シナプス / シナプス刈り込み / 生後発達 / 神経回路 / 逆行性シグナル / 小脳 / 登上線維 / マウス

Outline of Annual Research Achievements

平成29年度の計画全体としては、ほぼ計画通り順調に達成したが、平成29年7月に入手する予定であった遺伝子改変マウスの作製が想定以上に遅れ、2カ月遅れて平成29年9月にようやく入手できた。直ちにこの遺伝子改変マウスを交配して目的とする分子(IGF-1受容体を介するシグナルを抑制すると考えられる分子)のプルキンエ細胞特異的ノックアウトマウスの作出を開始したが、想定以上にマウスの妊娠率や出産率が悪く、平成29年度に計画していたシナプス刈り込みの機能解析実験に必要なプルキンエ細胞特異的ノックアウトマウスの個体数を得るのが困難になった。そこで十分な数のマウスを得るために、交配用のマウスの個体数を増やし、当初計画より繁殖期間を4ヶ月延長する必要が生じた(平成30年5月末まで)。さらにその後、このノックアウトマウスの機能解析と研究成果の取りまとめを行って、当初計画を終了するために、平成31年度に研究費を繰り越した。まず、生後20日から30日の当該分子のプルキンエ細胞特異的ノックアウトマウスから小脳スライスを作製し、プルキンエ細胞からホールセル記録を行った。登上線維を刺激した際に発生するシナプス応答から、プルキンエ細胞にシナプス結合する登上線維の本数を求め、さらにシナプス応答の振幅、およびキネティクスを解析した。その結果、登上線維シナプス刈り込みが障害されていることを確認した。以上の電気生理学的計測を終了し、データの取りまとめを行った。

Research Products

• [Journal Article] Monoacylglycerol lipase deficiency affects diet-induced obesity, fat absorption, and feeding behavior in CB1 cannabinoid receptor-deficient mice. (2019)
  • Author(s): Yoshida K, Kita Y, Tokuoka SM, Hamano F, Yamazaki M, Sakimura K, Kano M, Shimizu T
  • Journal Title: FASEB J Volume: 33 Pages: 2484-2497
  • DOI: 10.1096/fj.201801203R
  • Peer Reviewed
• [Journal Article] Hyperactivation of mTORC1 disrupts cellular homeostasis in cerebellar Purkinje cells. (2019)
  • Author(s): Sakai Y, Kassai H, Nakayama H, Fukaya M, Maeda T, Nakao K, Hashimoto K, Sakagami H, Kano M, Aiba A
  • Journal Title: Sci Rep Volume: 9 Pages: 2, 799
  • DOI: 10.1038/s41598-019-38730-4
  • Peer Reviewed / Open Access
• [Journal Article] Ectopic positioning of Bergmann glia and impaired cerebellar wiring in M1cl-overexpressing mice. (2018)
  • Author(s): Kikuchihara S, Sugio S, Tanaka KF, Watanabe T, Kano M, Yamazaki Y, Watanabe M, Ikenaka K
  • Journal Title: J Neurochem Volume: 147 Pages: 344-360
  • DOI: 10.1111/jnc.14486
  • Peer Reviewed
• [Journal Article] Supramammillary nucleus afferents to the dentate gyrus co-release glutamate and GABA and potentiate granule cell output. (2018)
  • Author(s): Hashimotodani Y, Karube F, Yanagawa Y, Fujiyama F, Kano M
  • Journal Title: Cell Rep Volume: 25 Pages: 2704-2715
  • DOI: 10.1016/j.celrep.2018.11.016
  • Peer Reviewed / Open Access
• [Journal Article] Control of excessive neural circuit excitability and prevention of epileptic seizures by endocannabinoid signaling. (2018)
  • Author(s): Sugaya Y, Kano M
  • Journal Title: Cell Mol Life Sci Volume: 75 Pages: 2793-2811
  • DOI: 10.1007/s00018-018-2834-8
  • Peer Reviewed
• [Journal Article] Multiple phases of climbing fiber synapse elimination in the developing cerebellum. (2018)
  • Author(s): Kano M, Watanabe T, Uesaka N, Watanabe M
  • Journal Title: Cerebellum Volume: 17 Pages: 722-734
  • DOI: 10.1007/s12311-018-0964-z
  • Peer Reviewed
• [Presentation] Molecular, cellular and circuit mechanisms of activity-dependent synapse elimination in the developing cerebellum (2019)
  • Author(s): Kano M
  • Organizer: International Symposium : Current Perspectives on Functional and Dysfunctional Neural Circuits
• [Presentation] Discovery and investigation of cerebellar long-term depression at Masao Ito's lab (2019)
  • Author(s): Kano M
  • Organizer: The 9th Federation of the Asian and Oceanian Physiological Societies Congress (第9回アジア・オセアニア生理学会連合2019年大会)
• [Presentation] Reduced synaptic inputs in prefrontal cortex by lack of a mental disorder-related epigenetic factor (2019)
  • Author(s): Nagahama K, Sakoori K, Watanabe T, Uesaka N, Kano M
  • Organizer: The 9th Federation of the Asian and Oceanian Physiological Societies Congress (第9回アジア・オセアニア生理学会連合2019年大会)
• [Presentation] Fndc3b promotes climbing fiber synapse elimination partly by inhibiting STAT3 in the cerebellum (2019)
  • Author(s): Kushibe K, Mercier C, Watanabe T, Miyazaki T, Yamasaki M, Watanabe M, Uesaka N, Kano M
  • Organizer: The 9th Federation of the Asian and Oceanian Physiological Societies Congress (第9回アジア・オセアニア生理学会連合2019年大会)
• [Presentation] Activity-dependent synapse elimination in the developing cerebellum (2019)
  • Author(s): Uesaka N, Kao TH, Kano M
  • Organizer: The 9th Federation of the Asian and Oceanian Physiological Societies Congress (第9回アジア・オセアニア生理学会連合2019年大会)
• [Presentation] Accelerated climbing fiber synapse elimination in cerebellar Purkinje cells lacking protocadherin 10 (2019)
  • Author(s): Watanabe T, Inoue S, Akamatsu T, Suzuki H, Abe M, Sakimura K, Uesaka N, Kano M
  • Organizer: The 9th Federation of the Asian and Oceanian Physiological Societies Congress (第9回アジア・オセアニア生理学会連合2019年大会)
• [Presentation] Modulation of dentate granule cell activity during fear memory extinction in freely moving mice (2019)
  • Author(s): Carrier-Ruiz A, Sugaya Y, Kano M
  • Organizer: The 9th Federation of the Asian and Oceanian Physiological Societies Congress (第9回アジア・オセアニア生理学会連合2019年大会)
• [Presentation] Neural circuit mechanisms of synapse elimination in the developing cerebellum (2018)
  • Author(s): Kano M
  • Organizer: The 9th International Symposium of the Society for Research on the Cerebellum and Ataxias
• [Presentation] Mechanisms underlying climbing fiber synapse elimination during postnatal cerebellar development (2018)
  • Author(s): Kano M
  • Organizer: The 75th FUJIHARA Seminar : Cerebellum as a CNS Hub - from its evolution to therapeutic strategy
• [Presentation] Neural circuit mechanisms underlying activity-dependent synapse elimination in the developing cerebellum (2018)
  • Author(s): Kano M
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society (第41回日本神経科学大会)
• [Presentation] Retrograde BDNF signaling required for synapse elimination in the developing cerebellum (2018)
  • Author(s): Choo M, Uesaka N, Watanabe M, Sakimura K, Kano M
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society (第41回日本神経科学大会)
• [Presentation] Impaired synapse development in mouse medial prefrontal cortex by deletion of a histone-modifying enzyme implicated in psyciatric disorder (2018)
  • Author(s): Nagahama K, Sakoori K, Watanabe T, Uesaka N, Kano M
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society (第41回日本神経科学大会)
• [Presentation] Roles of synaptic transmission in climbing fiber to Purkinje cell synapse elimination during postnatal cerebellar development (2018)
  • Author(s): Kao T-H, Matsuyama K, Uesaka N, Kano M
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society (第41回日本神経科学大会)
• [Presentation] Dentate granule cell activity during fear memory extinction in freely moving mice (2018)
  • Author(s): Carrier-Ruiz A, Sugaya Y, Kano M
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society (第41回日本神経科学大会)
• [Presentation] Near-infrared deep brain stimulation via upconversion nanoparticle-mediated optogenetics (2018)
  • Author(s): He L, Chen S, Zachary Weitemier A, Wang X, Tao Y, Huang AJY, Hashimotodani Y, Kano M, Iwasaki H, Parajuli LK, Okabe S, Tsutsui-Kimura I, F-Tanaka K, McHugh TJ
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society (第41回日本神経科学大会)
• [Presentation] Near-infrared deep brain stimulation via upconversion nanoparticle-mediated optogenetics (2018)
  • Author(s): Chen S, Weitemier AZ, Zeng X, HE L, Wang X, Tao Y, Huang A, Hashimotodani Y, Kano M, Iwasaki H, Parajuli LK, Okabe S, Loong D, All AH, Tsutsui-Kimura I, Tanaka KF, Liu X, Mchugh TJ
  • Organizer: Society for Neuroscience 2018 Annual Meeting
• [Presentation] Function of the adult-born neurons in memory consolidation during sleep (2018)
  • Author(s): Kumar D, Koyanagi I, Carrier-Ruiz A, Vergara P, Sugaya Y, Srinivasan S, Kasuya M, Yu T-S, Vogt K, Muratani M, Ohnishi T, Singh S, Teixeira CM, Nondhalee P, Naoi T, Mchugh TJ, Kernie SG, Kano M, Sakurai T, Yanagisawa M, Sakaguchi M
  • Organizer: Society for Neuroscience 2018 Annual Meeting
• [Presentation] Activity of cerebellar climbing fibers represents forelimb movements during voluntary lever-pull task in mice (2018)
  • Author(s): Hidaka N, Tsutsumi S, Ikezoe K, Isomura Y, Kano M, Kitamura K
  • Organizer: Society for Neuroscience 2018 Annual Meeting
• [Presentation] Organization of the functional inputs from the sensorimotor cortex to the cerebellum revealed by transcranial optogenetic mapping (2018)
  • Author(s): Choo M, Hira R, Matsuzaki M, Ikezoe K, Augustine GJ, Kano M, Kitamura K
  • Organizer: Society for Neuroscience 2018 Annual Meeting