Role of organelles in regulating presynaptic function

• Project/Area Number: 19K06901
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: The University of Tokyo
• Principal Investigator: Kobayashi Shizuka 東京大学, 医科学研究所, 助教 (50705879)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: シナプス可塑性 / 短期可塑性 / 海馬 / 細胞内小器官 / シナプス小胞 / 神経伝達物質 / シナプス伝達 / 小胞体 / 遺伝子改変マウス / プレシナプス

Outline of Research at the Start

細胞内オルガネラの一つである小胞体は、シナプス前終末内のシナプス小胞近傍に局在するだけでなく、エンドソームをはじめとする他の膜構造ともネットワークを形成するなど、従来の想定を超える分布形態を示すことが近年報告されているが、その機能的役割は不明な点が多い。そこで本研究では、シナプス前終末特異的な小胞体機能異常が、神経伝達物質放出やシナプス可塑性などの脳の生理機能に及ぼす影響を検討することで、小胞体のプレシナプスにおける機能を明らかにする。

Outline of Final Research Achievements

In this study, we tried to elucidate the functional roles of presynaptic endoplasmic reticulum (ER) on neurotransmission and presynaptic short-term plasticity. We generated presynaptic site-specific ER-resident regulatory proteins (Molecule A and B)- deficient mice and examined whether presynaptic ER influenced the release properties and short-term synaptic plasticity. In the electrophysiological analysis with hippocampal slices, presynaptic short-term plasticity was significantly changed in presynaptic site-specific Molecule A-deficient mice.

Academic Significance and Societal Importance of the Research Achievements

近年、アルツハイマー病やパーキンソン病の原因として小胞体におけるカルシウム調節の異常や脂質代謝の異常が相次いで指摘されているが、シナプス前終末における小胞体の生理的、機能的意義については不明な点が多いのが現状であった。本研究の成果により、シナプス前終末における小胞体の機能異常が神経伝達やシナプス可塑性に影響を及ぼすことが明らかになったことで、認知・記憶障害をはじめとする神経疾患の新たな発症機序の発見につながるという意義をもつ。

Research Products

• [Journal Article] SIPA1L1/SPAR1 Interacts with the Neurabin Family of Proteins and is Involved in GPCR Signaling (2022)
  • Author(s): Matsuura K., Kobayashi S., Konno K., Yamasaki M., Horiuchi T., Senda T., Hayashi T., Satoh K., Arima-Yoshida F., Iwasaki K., Negishi L., Yasui-Shimizu N., Kohu K., Kawahara S., Kirino Y., Nakamura T., Watanabe M., Yamamoto T., Manabe T. and Akiyama T.
  • Journal Title: The Journal of Neuroscience Volume: 42 Issue: 12 Pages: 2448-2473
  • DOI: 10.1523/jneurosci.0569-21.2022
  • Peer Reviewed / Open Access
• [Journal Article] Loss of calsyntenin paralogs disrupts interneuron stability and mouse behavior (2022)
  • Author(s): Mori Keita、Koebis Michinori、Nakao Kazuki、Kobayashi Shizuka、Kiyama Yuji、Watanabe Masahiko、Manabe Toshiya、Iino Yuichi、Aiba Atsu
  • Journal Title: Molecular Brain Volume: 15 Issue: 1 Pages: 23-23
  • DOI: 10.1186/s13041-022-00909-8
  • Peer Reviewed / Open Access
• [Journal Article] Impairment of spatial memory accuracy improved by Cbr1 copy number resumption and GABAB receptor-dependent enhancement of synaptic inhibition in Down syndrome model mice (2020)
  • Author(s): Arima-Yoshida Fumiko、Raveau Matthieu、Shimohata Atsushi、Amano Kenji、Fukushima Akihiro、Watanave Masashi、Kobayashi Shizuka、Hattori Satoko、Usui Masaya、Sago Haruhiko、Mataga Nobuko、Miyakawa Tsuyoshi、Yamakawa Kazuhiro、Manabe Toshiya
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 14187-14187
  • DOI: 10.1038/s41598-020-71085-9
  • Peer Reviewed / Open Access
• [Journal Article] Hyperactive and impulsive behaviors of LMTK1 knockout mice (2020)
  • Author(s): Takahashi Miyuki、Sugiyama Arika、Wei Ran、Kobayashi Shizuka、Fukuda Kimiko、Nishino Hironori、Takahashi Roka、Tsutsumi Koji、Kita Ichiro、Ando Kanae、Manabe Toshiya、Kamiguchi Hiroyuki、Tomomura Mineko、Hisanaga Shin-ichi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 15461-15461
  • DOI: 10.1038/s41598-020-72304-z
  • Peer Reviewed / Open Access
• [Journal Article] Protrudin-deficient mice manifest depression-like behavior with abnormalities in activity, attention, and cued fear-conditioning (2020)
  • Author(s): Shirane Michiko、Shoji Hirotaka、Hashimoto Yutaka、Katagiri Hiroyuki、Kobayashi Shizuka、Manabe Toshiya、Miyakawa Tsuyoshi、Nakayama Keiichi I.
  • Journal Title: Molecular Brain Volume: 13 Issue: 1 Pages: 146-146
  • DOI: 10.1186/s13041-020-00693-3
  • Peer Reviewed / Open Access
• [Journal Article] Lmtk3-KO Mice Display a Range of Behavioral Abnormalities and Have an Impairment in GluA1 Trafficking (2019)
  • Author(s): Montrose Kristopher、Kobayashi Shizuka、Manabe Toshiya、Yamamoto Tadashi
  • Journal Title: Neuroscience Volume: 414 Pages: 154-167
  • DOI: 10.1016/j.neuroscience.2019.06.033
  • Peer Reviewed
• [Journal Article] GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells (2019)
  • Author(s): Usui R, Yabe D, Fauzi M, Goto H, Botagarova A, Tokumoto S, Tatsuoka H, Tahara Y, Kobayashi S, Manebe T, Baba Y, Kurosaki T, Herrera PL, Ogura M, Nagashima K, Inagaki N
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 15562-15562
  • DOI: 10.1038/s41598-019-52048-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] GPR40 activation initiates store operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells. (2019)
  • Author(s): Usui R., Yabe D., Fauzi M., Goto H., Botagarova A., Tokumoto S., Tatsuoka H., Tahara Y., Kobayashi S. , Manabe T. , Baba Y., Kurosaki T., Herrera P., Ogura M., Nagashima K. and Inagaki N.
  • Organizer: American Diabetes Association (国際学会）
  • Int'l Joint Research