LGI1–ADAM22–MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention

• Fukata, Yuko

• Chen, Xiumin

• Chiken, Satomi

• Hirano, Yoko

• Yamagata, Atsushi

• Inahashi, Hiroki

• Sanbo, Makoto

• Sano, Hiromi

• Goto, Teppei

• Hirabayashi, Masumi

• Kornau, Hans-Christian

• Prüss, Harald

• Nambu, Atsushi

• Fukai, Shuya

• Nicoll, Roger A.

• Fukata, Masaki

抄録

Physiological functioning and homeostasis of the brain rely on finely tuned synaptic transmission, which involves nanoscale alignment between presynaptic neurotransmitter-release machinery and postsynaptic receptors. However, the molecular identity and physiological significance of transsynaptic nanoalignment remain incompletely understood. Here, we report that epilepsy gene products, a secreted protein LGI1 and its receptor ADAM22, govern transsynaptic nanoalignment to prevent epilepsy. We found that LGI1–ADAM22 instructs PSD-95 family membrane-associated guanylate kinases (MAGUKs) to organize transsynaptic protein networks, including NMDA/AMPA receptors, Kv1 channels, and LRRTM4–Neurexin adhesion molecules. Adam22ΔC5/ΔC5 knock-in mice devoid of the ADAM22–MAGUK interaction display lethal epilepsy of hippocampal origin, representing the mouse model for ADAM22-related epileptic encephalopathy. This model shows less-condensed PSD-95 nanodomains, disordered transsynaptic nanoalignment, and decreased excitatory synaptic transmission in the hippocampus. Strikingly, without ADAM22 binding, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Furthermore, forced coexpression of ADAM22 and PSD-95 reconstitutes nano-condensates in nonneuronal cells. Collectively, this study reveals LGI1–ADAM22–MAGUK as an essential component of transsynaptic nanoarchitecture for precise synaptic transmission and epilepsy prevention.

収録刊行物

• Proceedings of the National Academy of Sciences of the United States of America

  Proceedings of the National Academy of Sciences of the United States of America 118 (3), e2022580118-, 2021-01-19

  National Academy of Sciences

キーワード

• LGI1–ADAM22
• MAGUK
• AMPA receptor
• transsynaptic nanocolumn
• epilepsy

詳細情報

• CRID: 1050287363406575616
• NII論文ID: 120006976050
• ISSN: 00278424
• ISSN: 10916490
• DOI: 10.1073/pnas.2022580118
• HANDLE: 2433/261902
• Web Site: http://www.pnas.org/syndication/doi/10.1073/pnas.2022580118
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.2022580118
• 本文言語コード: ja
• 資料種別: journal article
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