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

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 nan...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 3
Main 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, Nicoll, Roger A, Fukata, Masaki
Format: Journal Article
Language:English
Published: United States 19.01.2021
Subjects:
ADAM Proteins - genetics
Animals
Brain - metabolism
Brain - pathology
Calcium-Binding Proteins - genetics
Disease Models, Animal
Epilepsy - genetics
Epilepsy - pathology
Epilepsy - prevention & control
Gene Knock-In Techniques
Guanylate Kinases - genetics
Hippocampus - metabolism
Hippocampus - pathology
Humans
Intracellular Signaling Peptides and Proteins - genetics
Membrane Proteins - genetics
Mice
Nerve Tissue Proteins - genetics
Neural Cell Adhesion Molecules - genetics
Receptors, AMPA - genetics
Receptors, N-Methyl-D-Aspartate - genetics
Shaker Superfamily of Potassium Channels - genetics
Synaptic Transmission - genetics
epilepsy
LGI1–ADAM22
AMPA receptor
MAGUK
transsynaptic nanocolumn
ISSN:1091-6490, 1091-6490
Online Access:Get more information
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Summary: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 channels, and LRRTM4-Neurexin adhesion molecules. 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.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.2022580118