title: Unified quantitative model of AMPA receptor trafficking at synapses.
abstract: Trafficking of AMPA receptors (AMPARs) plays a key role in synaptic transmission. However, a general framework integrating the two major mechanisms regulating AMPAR delivery at postsynapses (i.e., surface diffusion and internal recycling) is lacking. To this aim, we built a model based on numerical trajectories of individual AMPARs, including free diffusion in the extrasynaptic space, confinement in the synapse, and trapping at the postsynaptic density (PSD) through reversible interactions with scaffold proteins. The AMPAR/scaffold kinetic rates were adjusted by comparing computer simulations to single-particle tracking and fluorescence recovery after photobleaching experiments in primary neurons, in different conditions of synapse density and maturation. The model predicts that the steady-state AMPAR number at synapses is bidirectionally controlled by AMPAR/scaffold binding affinity and PSD size. To reveal the impact of recycling processes in basal conditions and upon synaptic potentiation or depression, spatially and temporally defined exocytic and endocytic events were introduced. The model predicts that local recycling of AMPARs close to the PSD, coupled to short-range surface diffusion, provides rapid control of AMPAR number at synapses. In contrast, because of long-range diffusion limitations, extrasynaptic recycling is intrinsically slower and less synapse-specific. Thus, by discriminating the relative contributions of AMPAR diffusion, trapping, and recycling events on spatial and temporal bases, this model provides unique insights on the dynamic regulation of synaptic strength.
authors.affiliation: Interdisciplinary Institute for Neuroscience,  University of Bordeaux, F-33000 Bordeaux,  France.
authors.forename: Katalin
authors.initials: K
authors.lastname: Czöndör
authors.forename: Magali
authors.initials: M
authors.lastname: Mondin
authors.forename: Mikael
authors.initials: M
authors.lastname: Garcia
authors.forename: Martin
authors.initials: M
authors.lastname: Heine
authors.forename: Renato
authors.initials: R
authors.lastname: Frischknecht
authors.forename: Daniel
authors.initials: D
authors.lastname: Choquet
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Sibarita
authors.forename: Olivier R
authors.initials: OR
authors.lastname: Thoumine
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D003198:Computer Simulation; D004058:Diffusion; D004705:Endocytosis; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D036681:Fluorescence Recovery After Photobleaching; D006624:Hippocampus / Q000166:cytology; D008566:Membranes / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D008959:Models, Neurological; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D057907:Post-Synaptic Density / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D008840:Microfilament Proteins; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; C104722:glutamate receptor ionotropic, AMPA 2