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It is well--established that Rab11-dependent recycling endosomes drive the activity-dependent delivery of AMPA receptors (AMPARs) into synapses during long-term potentiation (LTP). Nevertheless, the molecular basis for this specialized function of recycling endosomes is still unknown. Here, we have investigated RAB11FIP2 (FIP2 hereafter) as a potential effector of Rab11-dependent trafficking during LTP in rat hippocampal slices. Surprisingly, we found that FIP2 operates independently from Rab11 proteins, and acts as a negative regulator of AMPAR synaptic trafficking. Under basal conditions, FIP2 associates with AMPARs at immobile compartments, separately from recycling endosomes. Using shRNA-mediated knockdown, we found that FIP2 prevents GluA1 (encoded by the Gria1 gene) AMPARs from reaching the surface of dendritic spines in the absence of neuronal stimulation. Upon induction of LTP, FIP2 is rapidly mobilized, dissociates from AMPARs and undergoes dephosphorylation. Interestingly, this dissociation of the FIP2-AMPAR complex, together with FIP2 dephosphorylation, is required for LTP, but the interaction between FIP2 and Rab11 proteins is not. Based on these results, we propose a retention-release mechanism, where FIP2 acts as a gate that restricts the trafficking of AMPARs, until LTP induction triggers their release and allows synaptic delivery.

A retention-release mechanism based on Rab11-FIP2 for AMPA receptor synaptic delivery during long-term potentiation