Synaptotagmin-3 drives AMPA receptor endocytosis, depression of synapse strength, and forgetting

Effects of the peptide were occluded in Syt3 knockout mice, implicating Syt3 in a GluA2-3Y–dependent mechanism of AMPA receptor internalization. Our data give rise to a model in which Syt3 at postsynaptic endocytic zones is bound to AP-2 and BRAG2 in the absence of calcium. GluA2 could then accumulate at endocytic zones by binding Syt3 in response to increased calcium during neuronal activity. This would potentially bring GluA2 into close proximity to BRAG2, where a transient interaction could activate BRAG2 and Arf6, and promote endocytosis of receptors via clathrin and AP-2 (10, 32). PICK1 is also important for AMPA receptor endocytosis, raising the question of the interplay of Syt3 and PICK1.