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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 ( D   eff  ) 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  D   eff  . 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  D   eff   depending on the receptor density. Increase in binding causes consistent decrease in  D   eff   for low and moderate receptor density. For high density, binding increases  D   eff   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  D   eff  . Supporting earlier experimental observations are mentioned and implications of present findings to the experimental observations on AMPAR diffusion are also drawn.

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