Activity-dependent exocytosis of recycling endosomes that contain AMPA receptors in postsynaptic regions of hippocampal neurons occurs at microdomains enriched in the target SNARE [soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor] syntaxin 4 (Stx4). These Stx4-enriched domains are located near the postsynaptic density, and disrupting SNARE interactions involving Stx4 prevents the fusion of recycling endosomes that contain AMPA receptors in dendritic spines. AMPA receptor trafficking is important for long-term potentiation; thus, Stx4 is an essential postsynaptic component for synaptic plasticity in hippocampal neurons.