AMPA glutamate receptors (AMPARs) mediate fast excitatory synaptic transmission. Upon fast consecutive synaptic stimulation, transmission can be depressed. Recuperation from fast synaptic depression has been attributed solely to recovery of transmitter release and/or AMPAR desensitization. We show that AMPAR lateral diffusion, observed in both intact hippocampi and cultured neurons, allows fast exchange of desensitized receptors with naïve functional ones within or near the postsynaptic density. Recovery from depression in the tens of millisecond time range can be explained in part by this fast receptor exchange. Preventing AMPAR surface movements through cross-linking, endogenous clustering, or calcium rise all slow recovery from depression. Physiological regulation of postsynaptic receptor mobility affects the fidelity of synaptic transmission by shaping the frequency dependence of synaptic responses.The fidelity of synaptic transmission between coupled neurons depends on their ability to transmit activity over a wide range of frequencies. Because of the relative slowness of chemical transmission, synaptic transmission acts as a low-pass filter with a cutoff between 10 and 100 Hz (1). When a presynaptic cell is stimulated at repetitive short intervals, the postsynaptic response usually decreases over time, the rate of depression being faster as the stimulus frequency increases (2). Most studies explain paired-pulse depression (PPD) as a combination of depression of presynaptic glutamate release and intrinsic kinetic properties of postsynaptic AMPARs upon agonist binding (2). Return from depression is believed to arise from recovery of release, together with AMPAR exit from desensitization. This assumes that AMPARs are stable within the postsynaptic density (PSD). Dynamic imaging has shown that AMPARs are not static but diffuse rapidly at the surface of neurons, traveling micrometer distances per second by random movements both in the synaptic and extrasynaptic membranes (3-8). Traffic of AMPARs from and to synapses through endo/exocytosis takes place in tens of minutes (9, 10). However, lateral diffusion allows AMPARs to explore the synapse in the second range (6,8,11), which suggests that surface AMPAR trafficking might be implicated in faster processes.

Many synapses in the mature CNS are wrapped by a dense extracellular matrix (ECM). Using single-particle tracking and fluorescence recovery after photobleaching, we found that this net-like ECM formed surface compartments on rat primary neurons that acted as lateral diffusion barriers for AMPA-type glutamate receptors. Enzymatic removal of the ECM increased extrasynaptic receptor diffusion and the exchange of synaptic AMPA receptors. Whole-cell patch-clamp recording revealed an increased paired-pulse ratio as a functional consequence of ECM removal. These results suggest that the surface compartments formed by the ECM hinder lateral diffusion of AMPA receptors and may therefore modulate short-term synaptic plasticity.