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

被引：54

作者：

Fukata, Yuko ^{[1
,2
]}

Chen, Xiumin ^{[3
,4
]}

Chiken, Satomi ^{[2
,5
]}

Hirano, Yoko ^{[1
,6
]}

Yamagata, Atsushi ^{[7
]}

Inahashi, Hiroki ^{[1
]}

Sanbo, Makoto ^{[8
]}

Sano, Hiromi ^{[2
,5
]}

Goto, Teppei ^{[8
]}

Hirabayashi, Masumi ^{[2
,8
]}

Kornau, Hans-Christian ^{[9
,10
]}

Pruess, Harald ^{[9
,11
]}

Nambu, Atsushi ^{[2
,5
]}

Fukai, Shuya ^{[12
]}

Nicoll, Roger A. ^{[3
,4
]}

Fukata, Masaki ^{[1
,2
]}

机构：

[1] Natl Inst Nat Sci, Natl Inst Physiol Sci, Dept Mol & Cellular Physiol, Div Membrane Physiol, Okazaki, Aichi 4448787, Japan

[2] SOKENDAI Grad Univ Adv Studies, Sch Life Sci, Dept Physiol Sci, Okazaki, Aichi 4448585, Japan

[3] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA

[5] Natl Inst Nat Sci, Natl Inst Physiol Sci, Dept Syst Neurosci, Div Syst Neurophysiol, Okazaki, Aichi 4448585, Japan

[6] Univ Tokyo, Grad Sch Med, Dept Pediat, Tokyo 1138655, Japan

[7] RIKEN, Lab Prot Funct & Struct Biol, Ctr Biosyst Dynam Res, Yokohama, Kanagawa 2300045, Japan

[8] Natl Inst Nat Sci, Natl Inst Physiol Sci, Ctr Genet Anal Behav, Okazaki, Aichi 4448787, Japan

[9] German Ctr Neurodegenerat Dis DZNE, D-10117 Berlin, Germany

[10] Charite Univ Med Berlin, Neurosci Res Ctr, Cluster NeuroCure, D-10117 Berlin, Germany

[11] Charite Univ Med Berlin, Dept Neurol & Expt Neurol, D-10117 Berlin, Germany

[12] Kyoto Univ, Grad Sch Sci, Dept Chem, Kyoto 6068502, Japan

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2021年 / 118卷 / 03期

关键词：

LGI1-ADAM22; MAGUK; AMPA receptor; transsynaptic nanocolumn; epilepsy; LONG-TERM POTENTIATION; LIMBIC ENCEPHALITIS; LEUCINE-RICH; PROTEIN; LGI1; COMPLEXES; DENSITY; MATURATION; RECEPTORS; CHANNELS;

D O I：

10.1073/pnas.2022580118

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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, Kv(1) channels, and LRRTM4-Neurexin adhesion molecules. Adam22(Delta C5/Delta C5) 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.

引用

页数：12

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