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The roles of synaptic palmitoylation in epilepsy

Research Project

Project/Area Number 16K07078
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionNational Center of Neurology and Psychiatry

Principal Investigator

HAYASHI Takashi  国立研究開発法人国立精神・神経医療研究センター, 神経研究所 病態生化学研究部, 室長 (80547472)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords神経科学 / 脳神経疾患 / 脂質 / シグナル伝達 / 薬理学
Outline of Final Research Achievements

Excess synaptic AMPA receptors leads to epilepsy in response to seizure-inducible stimulation. Although proper regulation of AMPA receptors plays crucial roles in the maintenance of the excitatory/inhibitory (E/I) synaptic balance, detailed mechanisms of epilepsy still remains unclear. Our previous studies revealed that a key modification of AMPA receptors expression is the reversible post-translational palmitoylation. GluA1 palmitoylation-deficient mice showed elevated seizure susceptibility and neuronal activity. Disruption of the palmitoylation site was accompanied with up-regulation of GluA1 phosphorylation in the hippocampus and increase of GluA1 protein in the cortex. Furthermore, GluA1 palmitoylation functioned to suppress excessive spine enlargement in chemical LTP. Our findings indicate that abnormality in GluA1 palmitoylation is liable to lead hyperexcitability in the cerebrum that makes it difficult to maintain network stability, resulting in epileptic seizure.

Academic Significance and Societal Importance of the Research Achievements

これまで、興奮性シナプスにおける興奮性神経伝達物質受容体の修飾異常と、てんかん発症時のシナプス機能調節の破綻メカニズムとの因果関係は、十分に検討されてこなかった。本研究において、てんかんの発症にAMPA受容体の分子修飾が関わっている可能性を示したことで、新たな創薬標的が明らかになった。今後、パルミトイル化の様な、AMPA受容体の特定の分子修飾状態だけを調節する化合物が同定されれば、てんかん発作に関わる過剰興奮シナプスに選択的に作用し、より副作用の少ない新たな抗てんかん薬開発への発展が期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (22 results)

All 2018 2017 2016

All Journal Article (6 results) (of which Peer Reviewed: 6 results,  Open Access: 6 results,  Acknowledgement Compliant: 1 results) Presentation (15 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Book (1 results)

  • [Journal Article] Comparative analysis of palmitoylation sites of serotonin (5-HT) receptors in vertebrates.2018

    • Author(s)
      Kaizuka T, Hayashi T
    • Journal Title

      Neuropsychopharmacology Reports

      Volume: 38 Issue: 2 Pages: 75-85

    • DOI

      10.1002/npr2.12011

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Deficiency of AMPAR?Palmitoylation Aggravates Seizure Susceptibility2018

    • Author(s)
      Itoh Masayuki、Yamashita Mariko、Kaneko Masaki、Okuno Hiroyuki、Abe Manabu、Yamazaki Maya、Natsume Rie、Yamada Daisuke、Kaizuka Toshie、Suwa Reiko、Sakimura Kenji、Sekiguchi Masayuki、Wada Keiji、Hoshino Mikio、Mishina Masayoshi、Hayashi Takashi
    • Journal Title

      The Journal of Neuroscience

      Volume: 38 Issue: 47 Pages: 10220-10235

    • DOI

      10.1523/jneurosci.1590-18.2018

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Perturbed expression pattern of the immediate early gene Arc in the dentate gyrus of GluA1 C‐terminal palmitoylation‐deficient mice2018

    • Author(s)
      Itoh Masayuki、Okuno Hiroyuki、Yamada Daisuke、Yamashita Mariko、Abe Manabu、Natsume Rie、Kaizuka Toshie、Sakimura Kenji、Hoshino Mikio、Mishina Masayoshi、Wada Keiji、Sekiguchi Masayuki、Hayashi Takashi
    • Journal Title

      Neuropsychopharmacology Reports

      Volume: 39 Issue: 1 Pages: 61-66

    • DOI

      10.1002/npr2.12044

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evolutionary acquisition and divergence of vertebrate HCN2 palmitoylation.2017

    • Author(s)
      Itoh M, Kaizuka T, Hayashi T
    • Journal Title

      Neurotransmitter

      Volume: 4

    • DOI

      10.14800/nt.1603

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Conservation and phylogenetic stepwise changes of aquaporin (AQP) 4 palmitoylation in vertebrate evolution.2017

    • Author(s)
      Hayashi T
    • Journal Title

      Neurotransmitter

      Volume: 4

    • DOI

      10.14800/nt.1608

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evolutionarily conserved phosphorylation and palmitoylation-dependent regulation of dopamine D1-like receptors in vertebrates.2016

    • Author(s)
      Adachi T, Hayashi T
    • Journal Title

      Neurotransmitter

      Volume: 3

    • DOI

      10.14800/nt.1434

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] Evolution of palmitoylation sites of 5-HT (serotonin) receptors in vertebrates2018

    • Author(s)
      Takashi Hayashi
    • Organizer
      11th FENS Forum of Neuroscience
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 高ω3多価不飽和脂肪酸食摂取の抗うつ様効果には側坐核のドパミン神経系が関与する2018

    • Author(s)
      竹内 絵理、山田 大輔、斎藤 顕宜、伊藤 政之、林 崇 、山田 光彦、和田 圭司、関口 正幸
    • Organizer
      第41回日本神経科学大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ω3多価不飽和脂肪酸高含有餌摂取マウスにおける強制水泳試験無動時間の減少:腹側被蓋野-側坐核ドパミン神経系の関与2018

    • Author(s)
      竹内絵理、山田大輔、斎藤顕宜、伊藤政之、林 崇、山田光彦、和田圭司、関口正幸
    • Organizer
      日本脂質栄養学会第27回大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 興奮性シナプスにおける神経伝達物質受容体のパルミトイル化による膜局在制御2018

    • Author(s)
      林  崇
    • Organizer
      第40回日本生物学的精神医学会・第61回日本神経化学会大会 合同年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] パルミトイル化によるAMPA受容体制御の異常は発作感受性を上昇させる2018

    • Author(s)
      伊藤政之、金子雅規、阿部学、山崎真弥、夏目里恵、山田大輔、崎村建司、関口正幸、和田圭司、三品昌美、林 崇
    • Organizer
      第139回日本薬理学会関東部会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Deficiency of AMPA receptor-palmitoylation aggravates the seizure susceptibility2018

    • Author(s)
      Masayuki Itoh, Mariko Yamashita, Masaki Kaneko, Hiroyuki Okuno, Manabu Abe, Maya Yamazaki, Rie Natsume, Daisuke Yamada, Toshie Kaizuka, Reiko Suwa, Kenji Sakimura, Masayuki Sekiguchi, Keiji Wada, Mikio Hoshino, Masayoshi Mishina, Takashi Hayashi
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Perturbed expression pattern of the immediate early gene Arc in the dentate gyrus of GluA1 C-terminal palmitoylation deficient mice2018

    • Author(s)
      Masayuki Itoh, Hiroyuki Okuno, Daisuke Yamada, Mariko Yamashita, Manabu Abe, Rie Natsume, Toshie Kaizuka, Kenji Sakimura, Mikio Hoshino, Masayoshi Mishina, Keiji Wada, Masayuki Sekiguchi, Takashi Hayashi
    • Organizer
      2018年度 「次世代脳」プロジェクト 冬のシンポジウム
    • Related Report
      2018 Annual Research Report
  • [Presentation] パルミトイル化によるAMPA型グルタミン受容体の制御とその異常に伴うてんかん発作2017

    • Author(s)
      伊藤政之、山下真梨子、奥野浩行、阿部学、山崎真弥、夏目里恵、崎村建司、星野幹雄、三品昌美、林 崇
    • Organizer
      第90回日本薬理学会年会
    • Place of Presentation
      長崎市(長崎新聞文化ホール)
    • Year and Date
      2017-03-16
    • Related Report
      2016 Research-status Report
  • [Presentation] Disruption of AMPA receptor-palmitoylation leads excitatory/inhibitory imbalance and elevated seizure susceptibility2017

    • Author(s)
      伊藤政之,山下真梨子,山田大輔,奥野浩行,阿部学,山崎真弥,夏目里恵,金子雅規,貝塚利恵,崎村建司,関口正幸,和田圭司,星野幹雄,三品昌美,林 崇
    • Organizer
      第40回日本神経科学大会
    • Related Report
      2017 Research-status Report
  • [Presentation] 大脳異常興奮の抑制に関わるAMPA受容体パルミトイル化依存的なシナプス機能制御2017

    • Author(s)
      金子雅規,伊藤政之,山下真梨子,奥野浩行,阿部学,山崎真弥,夏目里恵,貝塚利恵,崎村建司,星野幹雄,三品昌美,林 崇
    • Organizer
      第47回日本神経精神薬理学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 興奮性/抑制性バランスの維持におけるパルミトイル化によるAMPA型グルタミン酸受容体制御の役割2017

    • Author(s)
      伊藤政之,山下真梨子,山田大輔,奥野浩行,阿部学,山崎真弥,夏目里恵,金子雅規,貝塚利恵,崎村建司,関口正幸,和田圭司,星野幹雄,三品昌美,林 崇
    • Organizer
      第137回日本薬理学会関東部会
    • Related Report
      2017 Research-status Report
  • [Presentation] Disruption of AMPA receptor-palmitoylation leads excitatory/inhibitory imbalance and elevated seizure susceptibility2017

    • Author(s)
      伊藤政之, 山下真梨子, 山田大輔, 奥野浩行, 阿部学, 山崎真弥, 夏目里恵, 金子雅規, 貝塚利恵, 崎村建司, 関口正幸, 和田圭司, 星野幹雄, 三品昌美, 林 崇
    • Organizer
      2017年度 「次世代脳」プロジェクト 冬のシンポジウム
    • Related Report
      2017 Research-status Report
  • [Presentation] AMPA受容体パルミトイル化による興奮性シナプスの機能維持とその異常に伴うてんかん発作2016

    • Author(s)
      伊藤政之、山下真梨子、奥野浩行、阿部学、山崎真弥、夏目里恵、崎村建司、星野幹雄、三品昌美、林 崇
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜市(パシフィコ横浜)
    • Year and Date
      2016-12-02
    • Related Report
      2016 Research-status Report
  • [Presentation] Maintenance of excitatory-inhibitory balance in brain by AMPA receptor palmitoylation2016

    • Author(s)
      山下真梨子、奥野浩行、阿部学、山崎真弥、夏目里恵、崎村建司、星野幹雄、三品昌美、林 崇
    • Organizer
      第39回日本神経科学大会
    • Place of Presentation
      横浜市(パシフィコ横浜)
    • Year and Date
      2016-07-21
    • Related Report
      2016 Research-status Report
  • [Presentation] グルタミン酸受容体パルミトイル化による興奮性/抑制性神経活動のバランス制御と抗てんかん薬の作用2016

    • Author(s)
      林 崇、山下真梨子、奥野浩行、阿部学、山崎真弥、夏目里恵、崎村建司、星野幹雄、三品昌美
    • Organizer
      第46回日本神経精神薬理学会年会
    • Place of Presentation
      韓国ソウル市COEX
    • Year and Date
      2016-07-03
    • Related Report
      2016 Research-status Report
  • [Book] 脳内環境辞典 担当項目「神経受容体のミクロイメージング」2017

    • Author(s)
      林 崇
    • Total Pages
      2
    • Publisher
      メディカルドゥ
    • Related Report
      2016 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

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