Elucidation of mechanisms for synapse site-specific regulation of synaptic plasticity by intracellular calcium dynamics

• Project/Area Number: 19H03321
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: The University of Tokyo
• Principal Investigator: Manabe Toshiya 東京大学, 医科学研究所, 教授 (70251212)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: カルシウム / シナプス伝達 / 長期増強 / 海馬 / 遺伝子改変マウス / シナプス可塑性 / 遺伝子改変 / マウス

Outline of Research at the Start

グルタミン酸は、シナプス前終末に活動電位が到達するとカルシウムチャネルからカルシウムが流入することで放出されるが、シナプス前終末では、カルシウムストアから放出されるカルシウムによっても修飾を受けると想定されている。シナプス後部では、NMDA受容体を介して流入するカルシウムによりシナプス可塑性が誘導される。本研究計画では、シナプス前終末およびシナプス後細胞特異的な遺伝子改変技術を用いて、カルシウムストアからのカルシウム放出を調節すると考えられている分子の役割を、分子レベル、細胞・ネットワークレベル、および、個体レベルで解明することを試みる。

Outline of Final Research Achievements

To elucidate the role of the functional molecule X in the regulation of calcium dynamics in the presynaptic terminal and postsynaptic cell in the central nervous system, we generated the gene-targeted mice lacking the molecule X specifically in the presynaptic terminal or postsynaptic cell and performed electrophysiological analyses using their acute hippocampal slices. We found the impairments in the excitatory synaptic responses to low-frequency stimulation in mutant mice lacking the molecule X presynaptically, suggesting the abnormality in recycling of synaptic vesicles, and in long-term potentiation of excitatory synaptic transmission in mutant mice lacking the molecule X postsynaptically.

Academic Significance and Societal Importance of the Research Achievements

小胞体からのカルシウムの放出がシナプス伝達やシナプス可塑性にどのように関与するかという報告はこれまでにあまりなかったが、シナプス部位特異的変異マウスを作製して電気生理学的な解析を進めることで、その重要性の一端を解明することができた。また、細胞内でのカルシウム放出の異常がハンチントン病やアルツハイマー病、パーキンソン病に関与するとされているが、この成果はこれらの精神神経疾患の病因解明のための基礎データを提供できるものと考える。

Research Products

• [Journal Article] Gastrin-releasing peptide regulates fear learning under stressed conditions via activation of the amygdalostriatal transition area (2022)
  • Author(s): Goto Fumiko、Kiyama Yuji、Ogawa Itone、Okuno Hiroyuki、Ichise Taeko、Ichise Hirotake、Anai Motonobu、Kodama Tatsuhiko、Yoshida Nobuaki、Bito Haruhiko、Manabe Toshiya
  • Journal Title: Molecular Psychiatry Volume: - Issue: 3 Pages: 1694-1703
  • DOI: 10.1038/s41380-021-01408-3
  • Peer Reviewed / Open Access
• [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] Cooperation of LIM domain-binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia. (2021)
  • Author(s): Ohnishi T, Kiyama Y, Arima-Yoshida F, Kadota M, Ichikawa T, Yamada K, Watanabe A, Ohba H, Tanaka K, Nakaya A, Horiuchi Y, Iwayama Y, Toyoshima M, Ogawa I, Shimamoto-Mitsuyama C, Maekawa M, Balan S, Arai M, Miyashita M, Toriumi K, et al.
  • Journal Title: EMBO Mol Med Volume: 13 Issue: 4
  • DOI: 10.15252/emmm.202012574
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model. (2019)
  • Author(s): Terumitsu-Tsujita M, Kitaura H, Miura I, Kiyama Y, Goto F, Muraki Y, Ominato S, Hara N, Simankova A, Bizen N, Kashiwagi K, Ito T, Toyoshima Y, Kakita A, Manabe T, Wakana S, Takebayashi H, Igarashi H
  • Journal Title: Ｊｏｕｒｎａｌ ｏｆ Ｎｅｕｒｏｃｈｅｍｉｓｔｒｙ Volume: jnc.14887 Issue: 1 Pages: 1-16
  • DOI: 10.1111/jnc.14887
  • Peer Reviewed / Open Access
• [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] Identification and characterization of the novel synaptic protein UF1 (2021)
  • Author(s): Chimura, T., Kiyama, Y., Ogawa, I. and Manabe, T.
  • Organizer: Japan Neuroscience Society, Annual Meeting
• [Presentation] Ldb2 modulates neuronal activities and fear learning by regulating Arc expression in the lateral nucleus of the amygdala (2021)
  • Author(s): Kiyama, Y., Ohnishi, T., Arima-Yoshida, F., Kadota, M., Bito, H., Kuraku, S., Yoshikawa, T., Manabe, T. and Okuno, H.
  • Organizer: Japan Neuroscience Society, Annual Meeting
• [Presentation] GPR40 activation initiates store operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic beta-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
  • Int'l Joint Research
• [Book] ギャノング生理学 原書26版：４章「興奮性組織：神経」 (2022)
  • Author(s): 真鍋俊也（岡田泰伸：監修）
  • Total Pages: 910
  • Publisher: 丸善出版
  • ISBN: 9784621307083
• [Remarks] 東京大学 医科学研究所 基礎医科学部門 神経ネットワーク分野
  • URL: https://www.ims.u-tokyo.ac.jp/NeuronalNetwork/Neuronal_Network/Index_japanese.htm
• [Remarks] 東京大学医科学研究所基礎医科学部門神経ネットワーク分野
  • URL: https://www.ims.u-tokyo.ac.jp/NeuronalNetwork/Neuronal_Network/Index_japanese.htm