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AMPA-type receptors (AMPARs) are rapidly inserted into synapses undergoing plasticity to increase synaptic transmission, but it is not fully understood if and how AMPAR-containing vesicles are selectively trafficked to these synapses. Here, we developed a strategy to label AMPAR GluA1 subunits expressed from their endogenous loci in cultured rat hippocampal neurons and characterized the motion of GluA1-containing vesicles using single-particle tracking and mathematical modeling. We find that GluA1-containing vesicles are confined and concentrated near sites of stimulation-induced structural plasticity. We show that confinement is mediated by actin polymerization, which hinders the active transport of GluA1-containing vesicles along the length of the dendritic shaft by modulating the rheological properties of the cytoplasm. Actin polymerization also facilitates myosin-mediated transport of GluA1-containing vesicles to exocytic sites. We conclude that neurons utilize F-actin to increase vesicular GluA1 reservoirs and promote exocytosis proximal to the sites of synaptic activity., Competing Interests: VW, PH, HL, DW, MD, ZL No competing interests declared, EO Erin K O'Shea is President of the Howard Hughes Medical Institute, one of the three founding funders of eLife, and a member of eLife's Board of Directors, (© 2024, Wong et al.)

The cytoskeletal organization of cells that are grown in tissue culture is often very different from that of cells in living organisms. This casts some doubt as to whether information that comes from studying actin-dependent cellular processes--such as cell motility or differentiation--in cells that are cultured under these conditions is physiologically relevant. Studies on cells grown in improved two-dimensional- and three-dimensional-culture systems that closely mimic the in vivo extracellular-matrix environment should provide a more accurate picture of actin-cytoskeletal function in the living organism.