The roles of synaptic palmitoylation in epilepsy
| Project/Area Number |
16K07078
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | National Center of Neurology and Psychiatry |
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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)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| 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)
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| Keywords | 神経科学 / 脳神経疾患 / 脂質 / シグナル伝達 / 薬理学 |
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| 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.
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| 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。
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Report
(4 results)
Research Products
(22 results)
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[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
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Journal Title
The Journal of Neuroscience
Volume: 38
Issue: 47
Pages: 10220-10235
DOI
Related Report
Peer Reviewed / Open Access
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[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
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[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
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[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
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