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Title: LGI1–ADAM22–MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention
Authors: 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  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-1241-1443 (unconfirmed)
Nicoll, Roger A.
Fukata, Masaki
Author's alias: 深田, 優子
知見, 聡美
平野, 瑶子
山形, 敦史
稲橋, 宏樹
三宝, 誠
佐野, 裕美
後藤, 鉄平
平林, 眞澄
南部, 篤
深井, 周也
深田, 正紀
Keywords: LGI1–ADAM22
MAGUK
AMPA receptor
transsynaptic nanocolumn
epilepsy
Issue Date: 19-Jan-2021
Publisher: National Academy of Sciences
Journal title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 118
Issue: 3
Thesis number: e2022580118
Abstract: 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.
Rights: © 2021 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
URI: http://hdl.handle.net/2433/261902
DOI(Published Version): 10.1073/pnas.2022580118
PubMed ID: 33397806
Appears in Collections:Journal Articles

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