VAMP4 Controls Constitutive Recycling and Sorting of Post-Synaptic Receptors in Neuronal Dendrites

Abstract

The endosomal recycling system dynamically tunes synaptic strength which underlies synaptic plasticity. Post-synaptic AMPA receptors exchange continuously between synaptic, extrasynaptic and intracellular compartments through diffusion in dendrites, endocytosis and recycling. Exocytosis is involved in the expression of long term potentiation (LTP), as post-synaptic expression of tetanus toxin, which cleaves the SNARE protein VAMP2, blocks LTP. Moreover, induction of LTP increases the exocytosis of transferrin receptors (TfR), markers of recycling endosomes (REs), as well as AMPARs. However, the interplay between AMPAR and TfR exocytosis in basal conditions and during LTP remains unclear. Here we identify VAMP4 as a prominent marker and the key vesicular SNARE protein that mediates most dendritic RE exocytosis. In contrast, VAMP2 labels only a small subset of REs. Knock-down (KD) of VAMP4 decreases TfR recycling but increases AMPAR recycling. In addition, VAMP4 KD increases AMPAR-mediated synaptic transmission, which consequently occludes LTP expression. The opposing changes in AMPAR and TfR recycling upon VAMP4 KD reveal their sorting into separate endosomal populations.