The role of AMPAR lateral diffusion in memory

The accumulation of AMPARs to synapses is a fundamental step in Long-term potentiation (LTP) of synaptic transmission, a well-established cellular correlate of learning and memory. The discovery of a sizeable and highly mobile population of extrasynaptic AMPARs - randomly scanning the synaptic surface under basal conditions - provided a conceptual framework for a simplified model: LTP can be induced by the capture, and hence accumulation, of laterally diffusing extrasynaptic AMPARs. Here, we review the evidence supporting a rate-limiting role of AMPAR lateral diffusion in LTP and as consequence, in learning and memory. We propose that there are "multiple solutions" for achieving the diffusional trapping of AMPAR during LTP, mainly mediated by the interaction between interchangeable AMPAR auxiliary subunits and cell-adhesion molecules containing PDZ-binding domains and synaptic scaffolds containing PDZ-domains. We believe that this molecular degeneracy in the diffusional trapping of AMPAR during LTP serve to ensure the robustness of this crucial step in the making of memories. All in all, the role of AMPAR lateral diffusion in LTP is not only a conceptual leap in our understanding of memory, but it might also hold the keys for the development of therapeutics against disorders associated with memory deficits such as Alzheimer's disease.