Self-crowding of AMPA receptors in the excitatory postsynaptic density can effectuate anomalous receptor sub-diffusion

AMPA receptors (AMPARs) and their associations with auxiliary transmembrane proteins are bulky structures with large steric-exclusion volumes. Hence, self-crowding of AMPARs, depending on the local density, may affect their lateral diffusion in the postsynaptic membrane as well as in the highly crowded postsynaptic density (PSD) at excitatory synapses. Earlier theoretical studies considered only the roles of transmembrane obstacles and the AMPAR-binding submembranous scaffold proteins in shaping receptor diffusion within PSD. Using lattice model of diffusion, the present study investigates the additional impacts of self-crowding on the anomalousity and effective diffusion coefficient (Deff) of AMPAR diffusion. A recursive algorithm for avoiding false self-blocking during diffusion simulation is also proposed. The findings suggest that high density of AMPARs in the obstacle-free membrane itself engenders strongly anomalous diffusion and severe decline in Deff. Adding transmembrane obstacles to the membrane accentuates the anomalousity arising from self-crowding due to the reduced free diffusion space. Contrarily, enhanced AMPAR-scaffold binding, either through increase in binding strength or scaffold density or both, ameliorates the anomalousity resulting from self-crowding. However, binding has differential impacts on Deff depending on the receptor density. Increase in binding causes consistent decrease in Deff for low and moderate receptor density. For high density, binding increases Deff as long as it reduces anomalousity associated with intense self-crowding. Given a sufficiently strong binding condition when diffusion acquires normal behavior, further increase in binding causes decrease in Deff. Supporting earlier experimental observations are mentioned and implications of present findings to the experimental observations on AMPAR diffusion are also drawn.Author summary: The transmembrane AMPA receptors (AMPARs) prominently exhibit lateral diffusion in the postsynaptic membrane at excitatory synapses. Steric obstructions to AMPAR diffusion due to the crowd of other relatively static transmembrane proteins and binding of AMPARs to the submembranous scaffold proteins in the specialized region of postsynaptic density (PSD) are well known to retard receptor diffusion, which causes receptor trapping and accumulation within PSD. However, AMPARs are significantly bulky structures and may also obstruct their own diffusion paths in the presence of their high density. It is shown here that intense self-crowding of AMPARs may lead to highly obstructed and confined receptor diffusion even in the obstacle-free medium, and the presence of other obstacles further aggravates this effect. AMPAR-scaffold binding reduces confined diffusion arising from self-crowding and strong binding engenders normal diffusion even at high receptor density. However, it overall causes reduction in the effective diffusion coefficient of the receptor diffusion.