Molecular mechanisms of activity dependent neural circuit refinement

• Project/Area Number: 15H05568
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Neurophysiology / General neuroscience
• Research Institution: The University of Tokyo
• Principal Investigator: Uesaka Naofumi 東京大学, 大学院医学系研究科(医学部), 助教 (70597624)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥23,400,000 (Direct Cost: ¥18,000,000、Indirect Cost: ¥5,400,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥13,390,000 (Direct Cost: ¥10,300,000、Indirect Cost: ¥3,090,000)
• Keywords: シナプス / シナプス刈り込み / 神経活動 / シナプス入力 / 登上線維 / プルキンエ細胞 / バーグマングリア / 小脳 / 分子機構 / 発達 / 神経活動依存性 / 分子メカニズム / 遺伝子操作 / スクリーニング

Outline of Final Research Achievements

In the postnatal development of animals,necessary synapses in the brain are strengthened and unnecessary synapses are weakened and eliminated. This process is known as synapse elimination and important for the conversion of immature neural circuit to mature version. In this study, I tried to elucidate roles of neural activity and its molecular basis in synapse elimination of the cerebellar climbing fiber to Purkinje cell synapse in the developing mouse.I found that the neural activity of climbing fiber is necessary to eliminate unnecessary synapses and to complete the innervation of Purkinje cells by necessary climbing fibers. I also found that BDNF promotes synapse elimination and Progranulin counteracts synapse elimination.

Research Products

• [Int'l Joint Research] RWTH Aachen(ドイツ)
• [Int'l Joint Research] Department of Anatomy and Cell Biology/University of Kansas, School of Medicine(米国)
• [Journal Article] Retrograde Signaling from Progranulin to Sort1 Counteracts Synapse Elimination in the Developing Cerebellum (2018)
  • Author(s): Uesaka N, Abe M, Konno K, Yamazaki M, Sakoori K, Watanabe T, Kao TH, Mikuni T, Watanabe M, Sakimura K and Kano M
  • Journal Title: Neuron Volume: 94（４）
  • Peer Reviewed
• [Journal Article] Presynaptic Mechanisms Mediating Retrograde Semaphorin Signals for Climbing Fiber Synapse Elimination During Postnatal Cerebellar Development (2018)
  • Author(s): Uesaka N, Kano M
  • Journal Title: Cerebellum Volume: 17 Issue: 1 Pages: 17
  • DOI: 10.1007/s12311-017-0888-z
  • Peer Reviewed
• [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 Issue: 1 Pages: 195-195
  • DOI: 10.1038/s41467-017-00260-w
  • Peer Reviewed / Open Access
• [Journal Article] The Metabotropic Glutamate Receptor Subtype 1 Mediates Experience-Dependent Maintenance of Mature Synaptic Connectivity in the Visual Thalamus (2016)
  • Author(s): Madoka Narushima, Motokazu Uchigashima, Yuki Yagasaki, Takeshi Harada, Yasuyuki Nagumo, Naofumi Uesaka, Kouichi Hashimoto, Atsu Aiba, Masahiko Watanabe, Mariko Miyata and Masanobu Kano
  • Journal Title: Neuron Volume: 91 Issue: 5 Pages: 1097
  • DOI: 10.1016/j.neuron.2016.07.035
  • Peer Reviewed / Open Access
• [Journal Article] Consensus Paper: class FormattedString { value: Cerebellar Development } (2015)
  • Author(s): Leto K, Arancillo M, Becker EB, Buffo A, Chiang C, Ding B, Dobyns WB, Dusart I, Haldipur P, Hatten ME, Hoshino M, Joyner AL, Kano M, Kilpatrick DL, Koibuchi N, Marino S, Martinez S, Millen KJ, Millner TO, Miyata T
  • Journal Title: Cerebellum Volume: 15 Issue: 6 Pages: 789
  • DOI: 10.1007/s12311-015-0724-2
  • URL: https://pure.teikyo.jp/en/publications/eaabf50b-e97f-47a3-bc59-077237c36e2b
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Roles of retrograde signaling in climbing fiber to Purkinje cell synapse elimination during postnatal cerebellar development (2017)
  • Author(s): Naofumi Uesaka and Masanobu Kano
  • Organizer: the 8th International Symposium of the Society for Research on the Cerebellum and Ataxia
  • Int'l Joint Research / Invited
• [Presentation] Regulation of climbing fiber synapse elimination in the developing cerebellum by retrograde signaling (2017)
  • Author(s): Naofumi Uesaka and Masanobu Kano
  • Organizer: 第４０回日本神経科学学会
  • Invited
• [Presentation] BDNF to TrkB signaling promotes climbing fiber synapse elimination in the developing cerebellum (2017)
  • Author(s): Myeong Jeong Choo,Taisuke Miyazaki, Maya Yamasaki, Meiko Kawamura, Takanobu Nakazawa, Asami Tanimura, Naofumi Uesaka, Masahiko Watanabe, Kenji Sakimura, Masanobu Kano
  • Organizer: 第４０回日本神経科学学会
• [Presentation] Involvement of Fndc3b, a fibronectin type III domain-containing protein, in climbing fiber synapse elimination during postnatal cerebellar development (2017)
  • Author(s): Celine Mercier, Takaki Watanabe, Taisuke Miyazaki, Masahiko Watanabe, Naofumi Uesaka, Masanobu Kano
  • Organizer: 第４０回日本神経科学学会
• [Presentation] Calcium channels in cerebellar synapses bind to extracellular ligand and organize presynaptic active zones (2017)
  • Author(s): Hiroshi Nishimune,Takafumi Mizushige, Naofumi Uesaka, Tomohiro Numata, Jie Chen, Badawi Yomna, Yomna Badawi, Yasuo Mori, Masanobu Kano
  • Organizer: 第４０回日本神経科学学会
• [Presentation] Screening of autism spectrum disorder-associated molecules that are involved in climbing fiber-Purkinje cell synapse elimination in the developing mouse cerebellum (2017)
  • Author(s): Takaki Watanabe, Shutaro Inoue, Naofumi Uesaka, Masanobu Kano
  • Organizer: 第４０回日本神経科学学会
• [Presentation] The frontotemporal dementia related gene, granulin regulates developmental synapse elimination in the cerebellum (2016)
  • Author(s): 上阪 直史、狩野 方伸
  • Organizer: 第９３回 日本生理学会大会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌）
  • Year and Date: 2016-03-22
• [Presentation] Type 1 metabotropic glutamate receptor maintains matu re retinogenicu late synaptic connectivity in the visual thalamus (2016)
  • Author(s): 鳴島 円、内ヶ島 基政、矢ヶ崎 有希、原田 武志、南雲 康之、上阪 直史、渡邉 貴樹、 橋本 浩一、饗場 篤、渡辺 雅彦、宮田 麻理子、狩野 方伸
  • Organizer: 第９３回 日本生理学会大会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌）
  • Year and Date: 2016-03-22
• [Presentation] Progranulin regulates climbing fiber synapse elimination during postnatal cerebellar development (2015)
  • Author(s): 上阪直史、阿部 学、山崎 真弥、今野 幸太郎、三國 貴康、渡辺 雅彦、崎村 建司、狩野 方伸
  • Organizer: 第３８回 日本神経科学大会
  • Place of Presentation: 神戸国際会議場（兵庫・神戸）
  • Year and Date: 2015-07-28
• [Presentation] Retrograde signaling involved in climbing fiber synapse elimination in the developing cerebellum (2015)
  • Author(s): 狩野方伸、上阪直史
  • Organizer: 第３８回 日本神経科学大会
  • Place of Presentation: 神戸国際会議場（兵庫・神戸）
  • Year and Date: 2015-07-28
  • Invited
• [Presentation] Knockdown of CNTNAP2 in neurons of the prefrontal cortex impairs synaptic function and causes impaired social behavior (2015)
  • Author(s): 酒井 浩旭 、佐郡 和人 、上阪 直史 、狩野 方伸
  • Organizer: 第３８回 日本神経科学大会
  • Place of Presentation: 神戸国際会議場（兵庫・神戸）
  • Year and Date: 2015-07-28
• [Presentation] Roles of neuroligin-2 in inhibitory synaptic transmission and climbing fiber synapse elimination in Purkinje cells during postnatal cerebellar development (2015)
  • Author(s): Suk King Lai、Naofumi Uesaka、Masanobu Kano
  • Organizer: 第３８回 日本神経科学大会
  • Place of Presentation: 神戸国際会議場（兵庫・神戸）
  • Year and Date: 2015-07-28
• [Presentation] 逆行性シグナルによる発達期シナプス刈り込みの制御 (2015)
  • Author(s): 上阪直史
  • Organizer: 生理研研究会「シナプスの構造構築と機能発現の分子基盤」
  • Place of Presentation: 生理学研究所（愛知・岡崎）
  • Year and Date: 2015-06-18
  • Invited
• [Remarks] ホームページ
  • URL: http://plaza.umin.ac.jp/~neurophy/Kano_Lab_j/Top_j.html
• [Remarks] 研究室ホームページ
  • URL: http://plaza.umin.ac.jp/~neurophy/Kano_Lab_j/Top_j.html