A single extracellular glycan links AMPA receptor gating to synaptic plasticity and memory persistence.

Authors

Ryosuke Midorikawa, Yoshihiko Wakazono, Sunita K C Basnet, Munal Babu Kandel, Taku Uchida, Jyoji Morise, Toru Yoshihara, Masahide Asano, Shogo Oka, Kogo Takamiya

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 36. Pages e2607934123. Sep 08, 2026. Epub Sep 01, 2026.

Abstract

Persistent synaptic plasticity is essential for memory, yet its stabilizing mechanisms remain incompletely understood. AMPA-type glutamate receptors (AMPARs) mediate most fast excitatory transmission in the brain, but how extracellular posttranslational modifications regulate their functional dynamics in vivo remains unclear. Here, we identify a single endogenous N-linked glycan at Asn401 of the AMPAR GluA1 subunit as a regulator that links receptor gating, membrane microdomain organization, and memory persistence. Loss of this glycan markedly reduced AMPAR desensitization and promoted resensitization. Biochemical and imaging analyses showed that GluA1 lacking the N401 glycan preferentially partitions into ganglioside-rich lipid raft microdomains through enhanced ganglioside binding, thereby disrupting activity-dependent receptor trafficking and promoting excessive receptor internalization. Using GluA1 N401Q knock-in mice, we show that loss of this glycan selectively impairs hippocampal long-term potentiation maintenance and compromises contextual and spatial memory persistence, while leaving learning acquisition largely intact. Notably, this site exhibits partial occupancy in the mammalian brain, indicating that it functions as an endogenous tunable constraint on synaptic stability. Together, these findings establish site-specific glycosylation as a mechanism that coordinates AMPAR gating with membrane compartmentalization to control persistent synaptic plasticity and memory in vivo.

PMID:
42679033
Bibliographic data and abstract were imported from PubMed on 02 Sep 2026.

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