Neuron type-specific regulatory mechanisms of the synapse

• Project/Area Number: 19H03331
• 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: National Institute for Physiological Sciences
• Principal Investigator: Fukata Yuko 生理学研究所, 分子細胞生理研究領域, 准教授 (40416186)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: シナプス / 興奮性神経 / 抑制性神経 / 興奮性シナプス伝達 / PSD-95 / てんかん

Outline of Research at the Start

我々の脳は生後、外界刺激依存的にシナプスを成熟、再編、安定化させて、視覚や言語などの脳高次機能を獲得する。この過程には、興奮性神経細胞と抑制性神経細胞間に形成されるシナプス結合の精緻なバランスが必要不可欠である。興奮性神経細胞と抑制性神経細胞における興奮性シナプスは、形態や反応様式が大きく異なっているが、これまでの研究は、主に興奮性神経細胞における興奮性シナプスの制御機構に焦点が当てられていた。本研究では、未だ不明な点が多い「抑制性神経細胞における興奮性シナプスのシナプス成熟・再編機構」を明らかにし、興奮性シナプスの細胞種特異性が生み出される分子機構を解明する。

Outline of Final Research Achievements

After birth, our brain acquires higher brain functions such as vision and language by maturing, reorganizing and stabilizing synapses in response to external stimuli. A finely-tuned balance of synaptic connections between excitatory and inhibitory neurons is essential for this process. In this study, we revealed an essential regulatory mechanism for excitatory synaptic transmission. We also found that dysfunction of this mechanism either in excitatory neurons or in inhibitory neurons commonly causes epileptic disorders in mouse.

Academic Significance and Societal Importance of the Research Achievements

本研究では、神経細胞種を区別したアプローチにより、興奮性シナプス伝達機構には、興奮性、抑制性神経細胞共通のシステムが存在し、いずれが破綻しても共通の脳病態を惹起することが明らかになった。本研究で得られたリソース（てんかんのマウスモデルなど）や手法は、今後、細胞種ごとのシナプス特性の研究に有効に使用されると期待できる。興奮性シナプス伝達機構の異種細胞間の共通点、相違点が明確になることで脳の発達・機能や病態の理解につながるものと考えられる。

Research Products

• [Int'l Joint Research] The University of Edinburgh/UCL(英国)
• [Int'l Joint Research] UCSF(米国)
• [Int'l Joint Research] DZNE/Charite-Universitatsmedizin(ドイツ)
• [Int'l Joint Research] Aarhus University(デンマーク)
• [Int'l Joint Research] Erasmus University/Leiden University(オランダ)
• [Int'l Joint Research]
• [Int'l Joint Research] UCSF/UCSD(米国)
• [Int'l Joint Research] DZNE(ドイツ)
• [Int'l Joint Research] IST(オーストリア)
• [Int'l Joint Research] UCL/The University of Edinburgh(英国)
• [Int'l Joint Research] University of Helsinki(フィンランド)
• [Int'l Joint Research] UCSF/Chicago University(米国)
• [Int'l Joint Research] Institut Curie(フランス)
• [Int'l Joint Research] DZNE(ドイツ)
• [Int'l Joint Research] UCL Institute of Neurology(英国)
• [Int'l Joint Research] University of Helsinki(フィンランド)
• [Int'l Joint Research]
• [Journal Article] Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy (2022)
  • Author(s): van der Knoop M Marieke M*、Maroofian Reza*、Fukata Yuko*、van Ierland Yvette、Karimiani G Ehsan、Lehesjoki Anna-Elina、Muona Mikko、Paetau Anders、Miyazaki Yuri、Hirano Yoko、Selim Laila、-----32名-----、Striano Pasquale、Severino Mariasavina、Fukata Masaki#、Hilhorst-Hofstee Yvonne#、Houlden Henry#
  • Journal Title: Brain Volume: - Issue: 7 Pages: 2301-2312
  • DOI: 10.1093/brain/awac116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice (2021)
  • Author(s): Norihiko Yokoi, Yuko Fukata, Kei Okatsu, Atsushi Yamagata, Yan Liu , Makoto Sanbo, Yuri Miyazaki, Teppei Goto, Manabu Abe , Hidetoshi Kassai, Kenji Sakimura, Dies Meijer, Masumi Hirabayashi, Shuya Fukai, Masaki Fukata
  • Journal Title: Cell Reports Volume: 37 Issue: 11 Pages: 110107-110107
  • DOI: 10.1016/j.celrep.2021.110107
  • NAID: 120007177780
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MAGUKs are essential, but redundant, in long-term potentiation (2021)
  • Author(s): Chen Xiumin、Fukata Yuko、Fukata Masaki、Nicoll Roger A.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 28
  • DOI: 10.1073/pnas.2107585118
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Trans-synaptic LGI1-ADAM22?MAGUK in AMPA and NMDA receptor regulation (2021)
  • Author(s): Fukata Yuko、Hirano Yoko、Miyazaki Yuri、Yokoi Norihiko、Fukata Masaki
  • Journal Title: Neuropharmacology Volume: 194 Pages: 108628-108628
  • DOI: 10.1016/j.neuropharm.2021.108628
  • Peer Reviewed / Open Access
• [Journal Article] A novel red fluorescence dopamine biosensor selectively detects dopamine in the presence of norepinephrine in vitro (2021)
  • Author(s): Nakamoto Chihiro、Goto Yuhei、Tomizawa Yoko、Fukata Yuko、Fukata Masaki、Harpsoe Kasper、Gloriam David E.、Aoki Kazuhiro、Takeuchi Tomonori
  • Journal Title: Molecular Brain Volume: 14 Issue: 1 Pages: 173-173
  • DOI: 10.1186/s13041-021-00882-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Encephalitis patient-derived monoclonal GABAa receptor antibodies cause epileptic seizures (2021)
  • Author(s): Kreye Jakob、Wright K Sukhvir、van Casteren Adriana、Stoffler Laura、Machule Marie-Luise、Reincke S Momsen、Nikolaus Marc、van Hoof Scott、Sanchez-Sendin Elisa、Homeyer A Marie、Cordero Gomez Cesar、Kornau Hans-Christian、-----12名-----、Wickel Jonathan、Geis Christian、Fukata Yuko、Fukata Masaki、Pruss Harald
  • Journal Title: Journal of Experimental Medicine Volume: 218
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention (2021)
  • Author(s): Fukata Yuko、Chen Xiumin、Chiken Satomi、Hirano Yoko、Yamagata Atsushi、Inahashi Hiroki、Sanbo Makoto、Sano Hiromi、Goto Teppei、Hirabayashi Masumi、Kornau Hans-Christian、Pruss Harald、Nambu Atsushi、Fukai Shuya、Nicoll Roger A.、Fukata Masaki
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 3 Pages: 1-12
  • DOI: 10.1073/pnas.2022580118
  • NAID: 120006976050
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice (2021)
  • Author(s): Yoshida T, Yamagata A, Imai A, Kim J, Izumi H, Nakashima S, Shiroshima T, Maeda A, Iwasawa-Okamoto S, Azechi K, Osaka F, Saitoh T, Maenaka K, Shimada T, Fukata Y, Fukata M, Matsumoto J, Nishijo H, Takao K, Tanaka S, Okabe S, Tabuchi K, Uemura T, Mishina M, Mori H & Fukai S
  • Journal Title: Nature Communications Volume: 12(1) Issue: 1 Pages: 1848-1848
  • DOI: 10.1038/s41467-021-22059-6
  • NAID: 120006996978
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Encephalitis patient derived monoclonal GABAA receptor antibodies cause catatonia and epileptic seizures (2021)
  • Author(s): Kreye Jakob、Wright Sukhvir K.、van Casteren Adriana、Machule Marie-Luise、Reincke S. Momsen、Nikolaus Marc、Stoffler Laura、van Hoof Scott、Sanchez-Sendin Elisa、Kornau Hans-Christian、Kaindl Angela M.、Wilson Max A.、Greenhill Stuart、他5名、Geis Christian、Fukata Yuko、Fukata Masaki、Pruss Harald
  • Journal Title: bioRxiv Volume: -
  • DOI: 10.1101/2021.01.28.428602
  • Open Access / Int'l Joint Research
• [Journal Article] APEGS法によるタンパク質パルミトイル化修飾の定量 (2021)
  • Author(s): 深田正紀、横井紀彦、深田優子
  • Journal Title: 電気泳動 Volume: 65
  • NAID: 130008072916
  • Peer Reviewed
• [Journal Article] Forelimb movements evoked by optogenetic stimulation of the macaque motor cortex (2020)
  • Author(s): Watanabe H, Sano H, Chiken S, Kobayashi K, Fukata Y, Fukata M, Mushiake H, Nambu A
  • Journal Title: Nat Commun Volume: 11 Issue: 1 Pages: 3253-3253
  • DOI: 10.1038/s41467-020-16883-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A genetically encoded red fluorescence dopamine biosensor enables dual imaging of dopamine and norepinephrine (2020)
  • Author(s): Nakamoto Chihiro、Goto Yuhei、Tomizawa Yoko、Fukata Yuko、Fukata Masaki、Harpsoe Kasper、Gloriam David E.、Aoki Kazuhiro、Takeuchi Tomonori
  • Journal Title: bioRxiv Volume: -
  • DOI: 10.1101/2020.05.25.115162
  • Open Access / Int'l Joint Research
• [Journal Article] The extracellular domain of angulin-1 and palmitoylation of its cytoplasmic region are required for angulin-1 assembly at tricellular contacts (2020)
  • Author(s): Yukako Oda, Taichi Sugawara, Yuko Fukata, Yasushi Izumi, Tetsuhisa Otani, Tomohito Higashi, Masaki Fukata, Mikio Furuse
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 13 Pages: 4289-4302
  • DOI: 10.1074/jbc.ra119.010491
  • Peer Reviewed / Open Access
• [Journal Article] Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability (2020)
  • Author(s): Kornau Hans‐Christian、Kreye Jakob、Stumpf Alexander、Fukata Yuko、Parthier Daniel、Sammons Rosanna P.、Imbrosci Barbara、Kurpjuweit Sarah、Kowski Alexander B.、Fukata Masaki、Pruss Harald、Schmitz Dietmar
  • Journal Title: Annals of Neurology Volume: 87 Issue: 3 Pages: 405-418
  • DOI: 10.1002/ana.25666
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6 (2019)
  • Author(s): Sada Ryota、Kimura Hirokazu、Fukata Yuko、Fukata Masaki、Yamamoto Hideki、Kikuchi Akira
  • Journal Title: Science Signaling Volume: 12 Issue: 608 Pages: 9519-9519
  • DOI: 10.1126/scisignal.aat9519
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ABHD10 is an S-depalmitoylase affecting redox homeostasis through peroxiredoxin-5 (2019)
  • Author(s): Cao Yang、Qiu Tian、Kathayat Rahul S.、Azizi Saara-Anne、Thorne Anneke K.、Ahn Daniel、Fukata Yuko、Fukata Masaki、Rice Phoebe A.、Dickinson Bryan C.
  • Journal Title: Nature Chemical Biology Volume: 15 Issue: 12 Pages: 1232-1240
  • DOI: 10.1038/s41589-019-0399-y
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Targeting CCR5 trafficking to inhibit HIV-1 infection (2019)
  • Author(s): Boncompain Gaelle、Herit Floriane、Tessier Sarah、Lescure Aurianne、Del Nery Elaine、Gestraud Pierre、Staropoli Isabelle、Fukata Yuko、Fukata Masaki、Brelot Anne、Niedergang Florence、Perez Franck
  • Journal Title: Science Advances Volume: 5 Issue: 10
  • DOI: 10.1126/sciadv.aax0821
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Systematic Screening of Depalmitoylating Enzymes and Evaluation of Their Activities by the Acyl-PEGyl Exchange Gel-Shift (APEGS) Assay (2019)
  • Author(s): Kanadome T, Yokoi N, Fukata Y, Fukata M.
  • Journal Title: Methods Mol Biol Volume: 印刷中 Pages: 83-98
  • DOI: 10.1007/978-1-4939-9532-5_7
  • ISBN: 9781493995318, 9781493995325
  • Peer Reviewed
• [Journal Article] Limbic Encephalitis in a Cat with Hippocampal Necrosis, putatively associated with DCC (deleted in colorectal cancer; Netrin-1 Receptor) Antibodies (2019)
  • Author(s): Hasegawa D, Ohnishi Y, Koyama E, Matsunaga S, Ohtani S, Nakanishi A, Shiga T, Chambers JK, Uchida K, Yokoi N, Fukata Y, Fukata M.
  • Journal Title: J Vet Intern Med Volume: 印刷中 Issue: 3 Pages: 1440-1445
  • DOI: 10.1111/jvim.15492
  • Peer Reviewed
• [Presentation] Trans-synaptic LGI1-ADAM22-MAGUK protein complex in synaptic functions and disorders (2021)
  • Author(s): Fukata Masaki、Fukata Yuko
  • Organizer: SYNABS Symposium (Germany, Virtual meeting)
  • Int'l Joint Research / Invited
• [Presentation] Acyl-PEGyl exchange gel-shift (APEGS) assay for palmitoylation quantification (2020)
  • Author(s): Fukata Masaki、Yokoi Norihiko、Fukata Yuko
  • Organizer: 第71回 日本電気泳動学会総会
• [Presentation] Synaptic function regulated by palmitate cycling on PSD-95 and trans-synaptic LGI1 and ADAM22 (2020)
  • Author(s): Fukata Masaki、Yuri Miyazaki、Yokoi Norihiko、Fukata Yuko
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] Physiological roles of trans-synaptic LGI1-ADAM22-MAGUK complex. (2019)
  • Author(s): Fukata Yuko、Hirano Yoko、Inahashi Hiroki、Miyazaki Yuri、Yokoi Norihiko、Sanbo Makoto、Goto Teppei、Hirabayashi Masumi、Fukata Masaki
  • Organizer: Neuroscience Meeting SfN 2019
  • Int'l Joint Research
• [Presentation] Functions of trans-synaptic protein complex of epilepsy-related ligand-receptor, LGI1 and ADAM22 (2019)
  • Author(s): Fukata Yuko
  • Organizer: McGill-NIPS Joint Workshop
  • Int'l Joint Research
• [Book] 膜タンパク質工学ハンドブック (2020)
  • Author(s): 平野瑶子、宮﨑裕理、横井紀彦、平田哲也、深田正紀、深田優子
  • Total Pages: 17
  • Publisher: エヌ・ティー・エス
  • ISBN: 9784860435370
• [Remarks] 研究室ホームページ
  • URL: https://www.nips.ac.jp/fukata/
• [Remarks] プレスリリース 新たなてんかん治療戦略を提案
  • URL: https://www.nips.ac.jp/release/2021/12/_adam22.html
• [Remarks] プレスリリース：神経シナプス間の軸調整を担う分子群を発見―新たなてんかん病態を解明―
  • URL: https://www.nips.ac.jp/release/2021/01/post_426.html