TY - JOUR
T1 - LGI1–ADAM22–MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention
AU - Fukata, Yuko
AU - Chen, Xiumin
AU - Chiken, Satomi
AU - Hirano, Yoko
AU - Yamagata, Atsushi
AU - Inahashi, Hiroki
AU - Sanbo, Makoto
AU - Sano, Hiromi
AU - Goto, Teppei
AU - Hirabayashi, Masumi
AU - Kornau, Hans Christian
AU - Prüss, Harald
AU - Nambu, Atsushi
AU - Fukai, Shuya
AU - Nicoll, Roger A.
AU - Fukata, Masaki
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Keiji Imoto (NINS) and Dr. Ryuichi Shigemoto (Institute of Science and Technology, Austria) for helpful discussions and suggestions; Ms. Yumiko Makino (Functional Genomics Facility, National Institute for Basic Biology Core Research Facilities) for technical assistance; and members of the M.F. and R.A.N. laboratories for support. This work was supported by grants from the Ministry of Education Culture, Sports, Science and Technology Grants 19H03331 and 19K22439 (to Y.F.), Grant 19H03162 (to A.Y.), Grant 15H05873 (to A.N.), Grant 18H03983 (to S.F.), and Grants 19H04974, 19K22548, 20H04915, and 20H00459 (to M.F.); Daiko Foundation (Y.F.); NIH Grant R01MH117139 (to R.A.N.); and the Hori Sciences and Arts Foundation (M.F.).
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/1/19
Y1 - 2021/1/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85099123197&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099123197&partnerID=8YFLogxK
U2 - 10.1073/pnas.2022580118
DO - 10.1073/pnas.2022580118
M3 - Article
C2 - 33397806
AN - SCOPUS:85099123197
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 3
M1 - e2022580118
ER -