Molecular mechanism of synapse maturation and pathophysiology of epilepsy

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H00459
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
• Research Institution: National Institute for Physiological Sciences
• Principal Investigator: Fukata Masaki 生理学研究所, 分子細胞生理研究領域, 教授 (00335027)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: シナプス / タンパク質 / 脂質 / 脳・神経 / ナノドメイン / ナノカラム / てんかん / 酵素

Outline of Final Research Achievements

To understand the physiology and pathology of the brain, it is essential to understand synapses, which are responsible for information transfer between neurons. Recently, many proteins involved in synapse formation have been reported, but the process by which immature synapses mature into functional synapses is not well understood. Here, we found that the LGI1-ADAM22-PSD-95 protein complex elaborately regulates synaptic transmission by aligning the nanodomains in the pre- and post-synapse. In addition, we found that disruption of the LGI1-ADAM22-PSD-95 pathway causes epileptic encephalopathy in humans and mice.

Free Research Field

神経科学、生化学、細胞生物学

Academic Significance and Societal Importance of the Research Achievements

従来の光学顕微鏡や電子顕微鏡を用いた解析では、シナプス内部やシナプス間隙をまたぐ分子の相互配置や動的変化に迫ることは困難であった。本研究では、超解像イメージング法や脳疾患モデルを用いて、シナプス内部のタンパク質の配置メカニズムを明らかにした。また、シナプス疾患をシナプスの形態や数の異常という従来の観点を超えて、シナプス-ナノドメインの構造・機能的変容として捉えた点も意義深い。