The roles of synaptic palmitoylation in epilepsy

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07078
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: National 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
• 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.

Free Research Field

神経化学・神経薬理学

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。