Functional significance of the intra-synaptic AMPA receptor density and its relationship to the metaplasticity of synaptic transmission

• Project/Area Number: 16H04662
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• 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): 石川 達也 金沢大学, 医学系, 助教 (00750209) ; 黒田 一樹 福井大学, 学術研究院医学系部門, 准教授 (60557966)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2018: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
• Keywords: シナプス伝達 / グルタミン酸受容体 / シナプス可塑性 / 電子顕微鏡 / 可塑性 / 受容体 / 分子局在 / 記憶形成 / メタ可塑性 / AMPA受容体 / シナプス / 学習

Outline of Final Research Achievements

This study revealed the expression pattern and density of AMPA type glutamate receptors (AMPARs) in three synaptic connections reported to possess a plastic changes in the transmission by employing highly quantitative SDS-FRL method. It also demonstrated significant but transient increase in AMPAR labeling density after the induction of long-term potentiation (LTP). The mutant mice having a gene modification in genes reported to be involved in the synaptic transmission and its plasticity such as GluA1, CaMKIIa and Arc showed significantly different AMPAR labeling density on average from those obtained from wild type mice. These results suggest that intra-synaptic AMPAR distribution is highly related to the metaplasticity of synaptic transmission.

Academic Significance and Societal Importance of the Research Achievements

本研究により、個体レベルで起きる学習機能や環境適応現象とシナプス可塑性との関係をこれまでより正確に統合できるようになる。更に、得られた知見をAMPAR局在調節を担う分子機構に関するこれまでの知見と統合することで、学習・記憶のメカニズムの研究に新しい概念や研究テーマを創出できる可能性がある。また、絶対量に迫るAMPAR発現密度の測定結果は、神経細胞の情報統合の理解、ひいては、脳の動作メカニズムのような複雑で現時点では実験的に扱うことができず、計算論的アプローチが必要な研究に有用な知見を提供することができる。また、記憶障害を伴う神経疾患の研究にも新たな解析基盤と視点を提供することもできる。

Research Products

• [Int'l Joint Research] Univer sity of Castilla La-Mancha(スペイン)
• [Int'l Joint Research] University of Pittsburgh(米国)
• [Int'l Joint Research] IST Austria(オーストラリア)
• [Int'l Joint Research] Castilla-La Mancha University(Spain)
• [Int'l Joint Research] IST Austria(Austria)
• [Int'l Joint Research] University of Pittsburgh Medical School(米国)
• [Journal Article] PIP3-Phldb2 is crucial for LTP regulating synaptic NMDA and AMPA receptor density and PSD95 turnover (2019)
  • Author(s): Xie Min-Jue、Ishikawa Yasuyuki、Yagi Hideshi、Iguchi Tokuichi、Oka Yuichiro、Kuroda Kazuki、Iwata Keiko、Kiyonari Hiroshi、Matsuda Shinji、Matsuzaki Hideo、Yuzaki Michisuke、Fukazawa Yugo、Sato Makoto
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 4305-4305
  • DOI: 10.1038/s41598-019-40838-6
  • Peer Reviewed / Open Access
• [Journal Article] Microglial SIRPα regulates the emergence of CD11c+ microglia and demyelination damage in white matter. (2019)
  • Author(s): Sato-Hashimoto M, Nozu T, Toriba R, Horikoshi A, Akaike M, Kawamoto K, Hirose A, Hayashi H, Nagai H, Shimizu W, Saiki A., Ishikawa T, Elhanbaly R, Kotani T, Murata Y, Saito Y, Naruse M, Shibasaki K, Oldenborg P.-A, Jung S, Matozaki T, Fukazawa Y, Ohnishi H.
  • Journal Title: eLife Volume: - Pages: 1-29
  • DOI: 10.7554/elife.42025
  • NAID: 120006604638
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Opposing roles of dopamine receptor D1- and D2-expressing neurons of the anteromedial olfactory tubercle in acquisition of place preference (2019)
  • Author(s): Koshi Murata, Tomoki Kinoshita, Yugo Fukazawa, Kenta Kobayashi, Akihiro Yamanaka, Takatoshi Hikida, Hiroyuki Manabe, and Masahiro Yamaguchi
  • Journal Title: Frontiers in Behavioral Neuroscience Volume: 13 Pages: 50-50
  • DOI: 10.3389/fnbeh.2019.00050
  • Peer Reviewed / Open Access
• [Journal Article] Layer-specific morphological and molecular differences in neocortical astrocytes and their dependence on neuronal layers (2018)
  • Author(s): Lanjakornsiripan Darin、Pior Baek-Jun、Kawaguchi Daichi、Furutachi Shohei、Tahara Tomoaki、Katsuyama Yu、Suzuki Yutaka、Fukazawa Yugo、Gotoh Yukiko
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1623-1623
  • DOI: 10.1038/s41467-018-03940-3
  • Peer Reviewed / Open Access
• [Journal Article] Elasticity-based boosting of neuroepithelial nukleokinesis via indirect energy transfer from mother to daughter (2018)
  • Author(s): Tomoyasu Shinoda, Arata Nagasaka, Yasuhiro Inoue, Ryo Higuchi, Yoshiaki Minami, Kagayaki Kato, Makoto Suzuki, Takefumi Kondo, Takumi Kawaue, Kanako Saito, Naoto Ueno, Yugo Fukazaawa, Masaharu Nagayama, Takashi Miura, Taiji Adachi, Takaki Miyata
  • Journal Title: PLoS Biology Volume: 16 Issue: 4 Pages: 2004426-2004426
  • DOI: 10.1371/journal.pbio.2004426
  • Peer Reviewed / Open Access
• [Journal Article] Optogenetic Control of Synaptic AMPA Receptor Endocytosis Reveals Roles of LTD in Motor Learning (2018)
  • Author(s): Kakegawa Wataru、Katoh Akira、Narumi Sakae、Miura Eriko、Motohashi Junko、Takahashi Akiyo、Kohda Kazuhisa、Fukazawa Yugo、Yuzaki Michisuke、Matsuda Shinji
  • Journal Title: Neuron Volume: 99 Issue: 5 Pages: 985-998
  • DOI: 10.1016/j.neuron.2018.07.034
  • Peer Reviewed / Open Access
• [Journal Article] SK2 Channels Associate With mGlu1α Receptors and CaV2.1 Channels in Purkinje Cells (2018)
  • Author(s): Lujan Rafael、Aguado Carolina、Ciruela Francisco、Arus Xavier Morato、Martin-Belmonte Alejandro、Alfaro-Ruiz Rocio、Martinez-Gomez Jesus、de la Ossa Luis、Watanabe Masahiko、Adelman John P、Shigemoto Ryuichi、Fukazawa Yugo
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 12 Pages: 311-311
  • DOI: 10.3389/fncel.2018.00311
  • Peer Reviewed / Open Access
• [Journal Article] Optogenetic Activation of Non-Nociceptive Aβ Fibers Induces Neuropathic Pain-LikeSensory and Emotional Behaviors after Nerve Injury in Rats. (2018)
  • Author(s): Tashima R, Koga K, Sekine M, Kanehisa K, Kohro Y, Tominaga K,Matsushita K, Tozaki-Saitoh H, Fukazawa Y, Inoue K, Yawo H, Furue H, Tsuda M
  • Journal Title: eNeuro Volume: 5(1) Issue: 1 Pages: 0450-17
  • DOI: 10.1523/eneuro.0450-17.2018
  • NAID: 130007901054
  • Peer Reviewed / Open Access
• [Journal Article] Differential association of GABAB receptors with their effector ion channels in Purkinje cells (2017)
  • Author(s): Lujan R, Aguado C, Ciruela F, Cozar J, Kleindienst D, de la Ossa L, Wickman K, Watanabe M, Shigemoto R, Fukazawa Y
  • Journal Title: Brain Structure and Function Volume: 223 Issue: 3 Pages: 565-1587
  • DOI: 10.1007/s00429-017-1568-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain. (2016)
  • Author(s): Kim SK, Hayashi H, Ishikawa T, Shibata K, Shigetomi E, Shinozaki Y, Inada H, Roh SE, Kim SJ, Lee G, Bae H, Moorhouse AJ, Mikoshiba K, Fukazawa Y, Koizumi S, Nabekura J.
  • Journal Title: J Clin Invest Volume: 126(5) Issue: 5 Pages: 1983-1997
  • DOI: 10.1172/jci82859
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] CAPS1 stabilizes the state of readily releasable synaptic vesicles to fusion competence at CA3-CA1 synapses in adult hippocampus (2016)
  • Author(s): 6.Shinoda Y, Ishii C, Fukazawa Y, Sadakata T, Ishii Y, Sano Y, Iwasato T, Itohara S, Furuichi T
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 31540-31540
  • DOI: 10.1038/srep31540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 凍結割断レプリカ標識法と免疫タグノックインを組合せた神経細胞におけるNa+/K+ ATPase alpha3の定量的膜上分布解析 (2019)
  • Author(s): 黒田一樹，石川達也，村田航志，深澤有吾
  • Organizer: 第124回日本解剖学会全国学術集会
• [Presentation] Construction rules of the axospinous synapses revealed by FIB-SEM imaging (2019)
  • Author(s): Yugo Fukazawa, Taito Sakurai, Ruwaida Elhanbaly, Tatsuya Ishikawa
  • Organizer: 9th Federation of the Asian and Oceanian Physiological Societies Congress
  • Int'l Joint Research
• [Presentation] Construction rules of the axospinous synapse revealed by quantitative electron microscopy and novel structural anomalies of the synapse in gene-mutated mouse lines (2018)
  • Author(s): Yugo Fukazawa
  • Organizer: 第41回日本神経科学大会
• [Presentation] Endosomal Q-SNARE Syntaxin 7 specifies a subpopulation of recycling synaptic vesicles preferentially responsive to high frequency stimulation (2018)
  • Author(s): Yasunori Mori, Yugo Fukazawa, Shigeo Takamori
  • Organizer: 第70回日本細胞生物学会大会
• [Presentation] 白質の損傷と修復を制御するミクログリアの分子シグナル (2018)
  • Author(s): 永井裕美，橋本美穂，堀越絢乃，Ruwaida Elhanbaly，石川達也，的崎尚，深澤有吾，大西浩史
  • Organizer: 第61回日本神経化学会大会
• [Presentation] 軸索-棘シナプス結合の微細構造相関解析とその応用 (2018)
  • Author(s): 深澤有吾, Elhanbaly Ruwaida, 石川達也
  • Organizer: 日本解剖学会総会全国学術集会
  • Invited
• [Presentation] 三次元走査型電子顕微鏡を用いた中枢神経系興奮性シナプス構造の定量的超微形態解析析 (2017)
  • Author(s): 深澤有吾、Elhanbaly Ruwaida、石川達也
  • Organizer: 第122回日本解剖学会 全国学術集会
  • Place of Presentation: 長崎大学医学部（長崎県長崎市）
  • Year and Date: 2017-03-21
• [Presentation] SDS-FRL法による定量的膜分子局在解析 (2017)
  • Author(s): 深澤有吾
  • Organizer: 日本細胞生物学会大会
  • Invited
• [Presentation] Common and Unique Ultrastructural Rules across Axospinous Synapses in the Mouse Brain Revealed by FIB-SEM Imaging (2017)
  • Author(s): Yugo Fukazawa
  • Organizer: Nepal-Japan Neurosymposium
  • Int'l Joint Research / Invited
• [Presentation] 凍結割断レプリカ免疫標識法を中心とした免疫電子顕微鏡法による分子局在解析の基礎と応用 (2017)
  • Author(s): 深澤有吾
  • Organizer: 新学術領域研究「先端モデル動物支援プラットフォーム」
  • Invited
• [Presentation] Quantitative morphological analysis of presynaptic fine structures in the mouse hippocampus by focused ion beam-scanning electron microscopy (2016)
  • Author(s): Yugo Fukazawa, Ruwaida Elhanbaly, Tatsuya Ishikawa
  • Organizer: 39th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-07-20
• [Book] Methods for immunoblot detection and electron microscopic localization of septin subunits in mammalian nervous systems (2016)
  • Author(s): Parajuli LK, Ageta-Ishihara N, Ageta H, Fukazawa Y, Kinoshita M
  • Total Pages: 9
  • Publisher: Academic Press
• [Remarks] 脳形態機能学（解剖学２）
  • URL: https://www.med.u-fukui.ac.jp/laboratory/brain/
• [Remarks] 福井大学医学部脳形態機能学（解剖学２）
  • URL: http://www-n.med.u-fukui.ac.jp/laboratory/brain/
• [Remarks] 福井大学医学部脳形態機能学（解剖学２）研究室
  • URL: http://kaibou2.med.lab.u-fukui.ac.jp/