Structural basis for GluA1 AMPA receptor regulation by PRRT1/SynDIG4 in LTP

AMPA receptor (AMPAR) signalling underlies long-term potentiation (LTP), a cellular mechanism for learning that selectively involves GluA1-type AMPARs through incompletely understood mechanisms. Here, we report a key role for the auxiliary subunit PRRT1/SynDIG4 in LTP. Cryo-EM structures of hippocampal AMPARs reveal preferential association of PRRT1 with GluA1 via its membrane-embedded CD225 domain, which sequesters the GluA1 C-terminus through a previously unexplored lipid modification on Cys825. Consequently, GluA1 regulatory motifs implicated in LTP, including the CaMKII binding site, are inaccessible. PRRT1 overexpression impairs LTP, which is rescued by the Cys825Ser mutation, presumably by restoring access of the GluA1 tail to Ser831 phosphorylation by CaMKII. Our data uncover a mechanism wherein PRRT1/SynDIG4 controls the availability of the GluA1 pool that is released upon the induction of LTP.