Investigation of molecular mechanisms underlying cooperative construction of pre- and postsynaptic compartments by an originally developed ultrastructure correlation analysis

• Project/Area Number: 19H03323
• 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: University of Fukui
• Principal Investigator: Fukazawa Yugo 福井大学, 学術研究院医学系部門, 教授 (60343745)
• Co-Investigator(Kenkyū-buntansha): 松井 広 東北大学, 生命科学研究科, 教授 (20435530) ; 黒田 一樹 福井大学, 学術研究院医学系部門, 准教授 (60557966) ; 加藤 輝 大学共同利用機関法人自然科学研究機構(新分野創成センター、アストロバイオロジーセンター、生命創成探究, 生命創成探究センター, 特任助教 (30391915)
• 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: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: シナプス結合 / 超微形態 / 三次元再構築 / 構造ー機能相関 / 構造-機能相関

Outline of Research at the Start

シナプス前後構造の接着に関与するシナプス接着分子を中心に遺伝子改変マウスのシナプス構造を解析し、シナプス前後構造の協調的な構築を支える分子を同定する。更に、これらの遺伝子改変マウスの単一シナプスレベルの機能的特徴を電気生理学的に明らかにすることで、各シナプス微細構造の機能との対応関係を明らかにする。また、精神神経疾患モデルマウスのシナプス構造を解析し、シナプス前後構造の協調的な構築機構の破綻と精神神経疾患の発症との関連性を明らかにすることで、病態解明と治療法開発の一助とする。

Outline of Final Research Achievements

The purpose of this study was to clarify the molecular mechanisms underlying the cooperative construction between pre- and postsynaptic structures and the common synaptic structural abnormalities among autism model mice, by an original analysis method that enables quantitative evaluation of the ultrastructure of the entire synaptic contact.We analyzed the synaptic structures of mice genetically modified for synaptic adhesion molecules and autism model mice. Our findings suggest that the lack of cooperative construction between pre- and postsynaptic structures is not a common ultrastructural anomaly in autism model mice. We will continue to analyze other gene-deficient mice and the differences in the interaction of wild-type NLG3 and R451C mutant NLG3 with Neurexin molecules for understanding the molecular mechanisms underlying the cooperative construction of pre- and postsynaptic structures.

Academic Significance and Societal Importance of the Research Achievements

シナプス伝達は脳の情報処理機構の基盤となる素過程であり、神経科学領域の重要な研究対象の一つである。また、自閉症を始めとする種々の精神疾患の原因の一つにシナプス機能異常が指摘されており、シナプス伝達の分子生物学的理解を深め、疾患発症との因果関係を明らかにする必要性が高まっている。本研究で開発応用したシナプス微細構造の新規解析法は、今後の学術的なシナプス研究に意義がある。また、この解析法は、他の神経疾患モデルマウスにも応用できるので、病態解明や治療法の開発を目指した基礎研究に応用でき、社会的に意義がある。

Research Products

• [Int'l Joint Research] オーストリア国立科学研究所/インスブルック大学(オーストリア)
• [Int'l Joint Research] University of Castilla-La Mancha(スペイン)
• [Int'l Joint Research] オーストリア国立科学研究所/インスブルック大学(オーストラリア)
• [Int'l Joint Research] University of Castilla-La Mancha(スペイン)
• [Int'l Joint Research] オーストリア国立科学研究所/インスブルック大学(オーストリア)
• [Int'l Joint Research] カスティーララマンチャ大学(スペイン)
• [Int'l Joint Research] ピッツバーグ大学(米国)
• [Int'l Joint Research] オックスフォード大学(英国)
• [Int'l Joint Research] フライブルグ大学(ドイツ)
• [Journal Article] Optogenetic stimulus-triggered acquisition of seizure resistance (2022)
  • Author(s): Shimoda Yoshiteru、Beppu Kaoru、Ikoma Yoko、Morizawa Yosuke M.、Zuguchi Satoshi、Hino Utaro、Yano Ryutaro、Sugiura Yuki、Moritoh Satoru、Fukazawa Yugo、Suematsu Makoto、Mushiake Hajime、Nakasato Nobukazu、Iwasaki Masaki、Tanaka Kenji F.、Tominaga Teiji、Matsui Ko
  • Journal Title: Neurobiology of Disease Volume: 163 Pages: 105602-105602
  • DOI: 10.1016/j.nbd.2021.105602
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transient astrocytic mGluR5 expression drives synaptic plasticity and subsequent chronic pain in mice (2022)
  • Author(s): Danjo Yosuke、Shigetomi Eiji、Hirayama Yukiho J.、Kobayashi Kenji、Ishikawa Tatsuya、Fukazawa Yugo、Shibata Keisuke、Takanashi Kenta、Parajuli Bijay、Shinozaki Youichi、Kim Sun Kwang、Nabekura Junichi、Koizumi Schuichi
  • Journal Title: Journal of Experimental Medicine Volume: 219 Issue: 4
  • DOI: 10.1084/jem.20210989
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Occludin and tricellulin facilitate formation of anastomosing tight-junction strand network to improve barrier function (2021)
  • Author(s): Saito Akira C.、Higashi Tomohito、Fukazawa Yugo、Otani Tetsuhisa、Tauchi Masashi、Higashi Atsuko Y.、Furuse Mikio、Chiba Hideki
  • Journal Title: Molecular Biology of the Cell Volume: 32 Issue: 8 Pages: 722-738
  • DOI: 10.1091/mbc.e20-07-0464
  • Peer Reviewed / Open Access
• [Journal Article] CAPS1 is involved in hippocampal synaptic plasticity and hippocampus-associated learning. (2021)
  • Author(s): Chiaki Ishii, Natsumi Shibano, Mio Yamazaki, Tomoki Arima, Yuna Kato, Yuki Ishii, Yo Shinoda, Yugo Fukazawa, Tetsushi Sadakata, Yoshitake Sano, Teiichi Furuichi.
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 1-15
  • DOI: 10.1038/s41598-021-88009-w
  • Peer Reviewed / Open Access
• [Journal Article] The Density of Group I mGlu5 Receptors Is Reduced along the Neuronal Surface of Hippocampal Cells in a Mouse Model of Alzheimer’s Disease (2021)
  • Author(s): Martin-Belmonte Alejandro、Aguado Carolina、Alfaro-Ruiz Rocio、Albasanz Jose Luis、Martin Mairena、Moreno-Martinez Ana Esther、Fukazawa Yugo、Lujan Rafael
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 11 Pages: 5867-5867
  • DOI: 10.3390/ijms22115867
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The endosomal Q-SNARE, Syntaxin 7, defines a rapidly replenishing synaptic vesicle recycling pool in hippocampal neurons (2021)
  • Author(s): Mori Yasunori、Takenaka Koh-ichiro、Fukazawa Yugo、Takamori Shigeo
  • Journal Title: Communications Biology Volume: 4 Issue: 1 Pages: 981-981
  • DOI: 10.1038/s42003-021-02512-4
  • Peer Reviewed / Open Access
• [Journal Article] Autistic-Like Behavior and Impairment of Serotonin Transporter and AMPA Receptor Trafficking in N-Ethylmaleimide Sensitive Factor Gene-Deficient Mice (2021)
  • Author(s): Xie Min-Jue、Iwata Keiko、Ishikawa Yasuyuki、Nomura Yuki、Tani Tomomi、Murata Koshi、Fukazawa Yugo、Matsuzaki Hideo
  • Journal Title: Frontiers in Genetics Volume: 12 Pages: 748627-748627
  • DOI: 10.3389/fgene.2021.748627
  • Peer Reviewed / Open Access
• [Journal Article] Density of GABAB receptors is reduced in granule cells of the hippocampus in a mouse model of Alzheimer´s disease (2020)
  • Author(s): Martin-Belmonte Alejandro, Aguado Carolina, Alfaro-Ruiz Rocio, Moreno-Martinez Esther Ana, de la Ossa Luis, Martinez-Hernandez Jose, Buisson Alain, Shigemoto Ryuichi, Fukazawa Yugo, Lujan Rafael
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 7 Pages: 2459-2459
  • DOI: 10.3390/ijms21072459
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deep learning-assisted high-throughput analysis of freeze-fracture replica images applied to glutamate receptors and calcium channels at hippocampal synapses (2020)
  • Author(s): Kleindienst David, Montanaro Jacqueline, Bhandari Pradeep, Case Matthew, Fukazawa Yugo, Shigemoto Ryuichi
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 18 Pages: 6737-6737
  • DOI: 10.3390/ijms21186737
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Age-dependent shift of AMPA receptors from synapses to intracellular compartments in Alzheimer´s disease: Immunocytochemical analysis of the CA1 hippocampal region in APP/PS1 transgenic mouse model (2020)
  • Author(s): Martin-Belmonte Alejandro, Aguado Carolina, Alfaro-Ruiz Rocio, Itakura Makoto, Moreno-Marinez Esther Ana, De La Ossa Luis, Molnar Elek, Fukazawa Yugo, Lujan Rafael
  • Journal Title: Frontiers in Aging Neuroscience Volume: 12
  • DOI: 10.3389/fnagi.2020.577996
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Region‐ and neuronal‐subtype‐specific expression of Na,K‐ATPase alpha and beta subunit isoforms in the mouse brain (2020)
  • Author(s): Murata Koshi、Kinoshita Tomoki、Ishikawa Tatsuya、Kuroda Kazuki、Hoshi Minako、Fukazawa Yugo
  • Journal Title: Journal of Comparative Neurology Volume: - Issue: 16 Pages: 2654-2678
  • DOI: 10.1002/cne.24924
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Life-Long Neural Stem Cells Are Fate-Specified at an Early Developmental Stage (2020)
  • Author(s): Tanaka Aoi、Ishida Shohei、Fuchigami Takahiro、Hayashi Yoshitaka、Kuroda Anri、Ikenaka Kazuhiro、Fukazawa Yugo、Hitoshi Seiji
  • Journal Title: Cerebral Cortex Volume: 30 Issue: 12 Pages: 6415-6425
  • DOI: 10.1093/cercor/bhaa200
  • Peer Reviewed
• [Journal Article] Distribution of mRNA for GPR143, a receptor of 3,4-L-dihydroxyphenylalanine, and of immunoreactivities for nicotinic acetylcholine receptors in the nigrostriatal and mesolimbic regions (2020)
  • Author(s): Kasahara Yuka、Masukawa Daiki、Nakamura Yoshie、Murata Koshi、Hashimoto Tatsuo、Takizawa Kohtaro、Koga Motokazu、Nakamura Fumio、Fukazawa Yugo、Funakoshi Kengo、Goshima Yoshio
  • Journal Title: Neuroscience Research Volume: - Pages: 370-375
  • DOI: 10.1016/j.neures.2020.08.003
  • Peer Reviewed
• [Journal Article] Geometry and the Organizational Principle of Spine Synapses along a Dendrite (2020)
  • Author(s): Parajuli Laxmi Kumar、Urakubo Hidetoshi、Takahashi-Nakazato Ai、Ogelman Roberto、Iwasaki Hirohide、Koike Masato、Kwon Hyung-Bae、Ishii Shin、Oh Won Chan、Fukazawa Yugo、Okabe Shigeo
  • Journal Title: eneuro Volume: 7 Issue: 6 Pages: 0248-20
  • DOI: 10.1523/eneuro.0248-20.2020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Advantages of Acute Brain Slices Prepared at Physiological Temperature in the Characterization of Synaptic Functions (2020)
  • Author(s): Eguchi Kohgaku、Velicky Philipp、Hollergschwandtner Elena、Itakura Makoto、Fukazawa Yugo、Danzl Johann Georg、Shigemoto Ryuichi
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 14 Pages: 63-63
  • DOI: 10.3389/fncel.2020.00063
  • NAID: 120006862680
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Physical disuse contributes to widespread chronic mechanical hyperalgesia, tactile allodynia, and cold allodynia through neurogenic inflammation and spino-parabrachio-amygdaloid pathway activation. (2020)
  • Author(s): Ohmichi Y, Ohmichi M, Tashima R, Osuka K, Fukushige K, Kanikowska D, Fukazawa Y, Yawo H, Tsuda M, Naito M, Nakano T.
  • Journal Title: Pain Volume: - Issue: 8 Pages: 1808-1823
  • DOI: 10.1097/j.pain.0000000000001867
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GABAergic neurons in the olfactory cortex projecting to the lateral hypothalamus in mice (2019)
  • Author(s): Murata K, Kinoshita T, Fukazawa Y, Kobayashi K, Kobayashi K, Miyamichi K, Okuno H, Bito H, Sakurai Y, Yamaguchi M, Mori K, Manabe H
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 7132-7132
  • DOI: 10.1038/s41598-019-43580-1
  • NAID: 120006862679
  • Peer Reviewed / Open Access
• [Journal Article] Pathological analysis of cadavers for educational dissection by using postmortem imaging (2019)
  • Author(s): Noriki Sakon、Iino Satoshi、Kinoshita Kazuyuki、Fukazawa Yugo、Inai Kunihiro、Sakai Toyohiko、Kimura Hirohiko
  • Journal Title: Pathology International Volume: 69 Issue: 10 Pages: 580-600
  • DOI: 10.1111/pin.12857
  • Peer Reviewed / Open Access
• [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
• [Presentation] 脳内におけるAMPA 受容体サブユニット構成解析法の確立と神経細胞膜上局在 (2022)
  • Author(s): 黒田 一樹、石川 達也、村田 航志、深澤 有吾
  • Organizer: 第127回日本解剖学会・全国学術集会
• [Presentation] Occludin and tricellulin jointly form a complex network of tight junction strands to maintain epithelial barrier (2021)
  • Author(s): Saito C Akira, Higashi Tomohito, Fukazawa Yugo, Otani Tetsuhisa, Tauchi Masashi, Higashi Y Atsuko, Furuse Mikio, Chiba Hideki
  • Organizer: ASCB Cell Bio virtual 2021
  • Int'l Joint Research
• [Presentation] NMDA receptor content of excitatory synapses in the CA1 region of the hippocampus is reduced in P301S mice (2021)
  • Author(s): Alfaro-Ruiz Rocio, Aguado Carolina, Marti-Belmonte Alejandro, Hernandez Felix, Moreno-Martinez Ana Esther, Avila Jesus, Fukazawa Yugo, Lujan Rafael
  • Organizer: SENC 2021
  • Int'l Joint Research
• [Presentation] Reduction in the density of group I mGluR5 receptirs along the neuronal surface of hippocampal cells in a mouse model of Alzheimer’s disease (2021)
  • Author(s): Martin-Belmonte Alejandro, Aguado Carolina, Alfaro-Ruiz Rocio, Albasanz Luis Jose, Martin Mairena, Moreno-Martinez Ana Esther, Fukazawa Yugo, Lujan Rafael
  • Organizer: SENC 2021
  • Int'l Joint Research
• [Presentation] 記憶固定化および長期記憶保持に寄与するポストシナプスのアクトミオシンとセプチンの協調 (2021)
  • Author(s): 上田(石原) 奈津実、深澤 有吾、高雄 啓三、見学 美根子、宮川 剛、井ノ口 馨、尾藤 晴彦、木下 専
  • Organizer: 第44回日本神経科学大会
• [Presentation] プロダイノルフィンおよびプレプロエンケファリンを発現するマウス嗅結節ニューロンの細胞種の同定 (2021)
  • Author(s): 村田 航志、黒田 一樹、深澤 有吾
  • Organizer: 第44回日本神経科学大会
• [Presentation] シナプス結合における協調的前後構造の構築を支える分子メカニズムの解析 (2021)
  • Author(s): 深澤 有吾、エルハンバリー ルワイダ、石川 達也、村田 航志、黒田 一樹
  • Organizer: 第44回日本神経科学大会
• [Presentation] プロダイノルフィンならびにプレプロエンケファリンを発現するマウス嗅結節ニューロン種の同定 (2021)
  • Author(s): 村田 航志、前川 文子、黒田 一樹、藤枝 重治、深澤 有吾
  • Organizer: 第127回日本解剖学会・全国学術集会
• [Presentation] FIB-SEM観察法によるシナプス結合における協調的前後構造の構築を支える分子メカニズムの解析 (2021)
  • Author(s): 深澤有吾、Elhanbaly Ruwaida、石川達也、村田航志、黒田一樹
  • Organizer: 第126回日本神経科学会全国学術集会・第98回日本生理学会大会 合同大会
• [Presentation] 神経細胞における凍結割断レプリカ標識法(SDS-FRL法)と免疫タグノックインを組み合わせたNAKα3を含むNa+/K+-ATPaseの定量的分布解析の最適化 (2021)
  • Author(s): 黒田一樹、石川達也、村田航志、深澤有吾
  • Organizer: 第126回日本神経科学会全国学術集会・第98回日本生理学会大会 合同大会
• [Presentation] Reduction of synaptic AMPA receptors in the CA1 region of the hippocampus in a mouse model of Alzheimer´s disease (2020)
  • Author(s): Martin-Belmonte A, Aguado C, Alfaro R, Moreno-Martinez R. AE, de la Ossa L, Molnar E, Fukazawa Y, Lujan R
  • Organizer: FENS 2020 Virtual Forum
  • Int'l Joint Research
• [Presentation] Density of GABAB receptors is reduced in granule cells of the hippocampus in a mouse model of Alzheimer´s disease (2020)
  • Author(s): Alfaro-Ruiz R, Aguado C, Martin-Belmonte A, Moreno-Martinez R. AE, de la Ossa L, Martinez-Hernandez J, Buisson A, Shigemoto R, Fukazawa Y, Lujan R
  • Organizer: FENS 2020 Virtual Forum
  • Int'l Joint Research
• [Presentation] 歯を含む硬組織における感覚受容関連分子の発現と局在についての解析基盤の確立 (2019)
  • Author(s): 4.領家崇、黒田一樹、村田航志、酒井涼、吉村仁志、佐野和生、深澤有吾
  • Organizer: 日本解剖学会 第79回中部支部学術集会
• [Remarks] 脳形態機能学（解剖学２）
  • URL: https://www.med.u-fukui.ac.jp/laboratory/brain/
• [Remarks] 院とラボ：神経科学分野：深澤研究室
  • URL: https://science-pass.com/2021/09/02/%E7%A5%9E%E7%B5%8C%E7%A7%91%E5%AD%A6%E5%88%86%E9%87%8E%EF%BC%9A%E6%B7%B1%E6%BE%A4%E7%A0%94%E7%A9%B6%E5%AE%A4/
• [Remarks] 福井大学医学部脳形態機能学分野
  • URL: https://www.med.u-fukui.ac.jp/laboratory/brain/
• [Patent(Industrial Property Rights)] 動物用の運動訓練評価装置 (2021)
  • Inventor(s): 深澤有吾, 酒井涼, 黒田一樹, 村田航志, 領家崇, 霊河秀樹
  • Industrial Property Rights Holder: 国立大学法人 福井大学
  • Industrial Property Rights Type: 実用新案
  • Filing Date: 2021
  • Acquisition Date: 2021