These results demonstrated that the lateral diffusion of AMPA receptors was a novel postsynaptic mechanism influencing short-term plasticity of individual synapses. Interestingly, the diffusion rates of AMPA receptors on dissociated hippocampal neurons

decreased during synapse maturation, between the second and third week in vitro (Borgdorff & Choquet, 2002). During this time period, a hyaluronan–CSPG-based ECM resembling the perisynaptic net-like ECM of the adult CNS is formed in these cultures (John et al., 2006). Similar to the in vivo situation, the net-like structure divides the neuronal surface into multiple compartments of variable size (Fig. 1, see above). These ECM-derived cell surface structures restrict the lateral diffusion of extrasynaptic AMPA receptors (Frischknecht et al., 2009).

Removal FDA-approved Drug Library mouse MK-1775 mouse of the ECM with the enzyme hyaluronidase increased diffusion rates of extrasynaptic receptors and the exchange rate between synaptic and extrasynaptic receptors. This resembles the ‘juvenile’ situation before the ECM is established in the cultures (day 10 in vitro). An electrophysiological examination revealed that removal of ECM from dissociated hippocampal neurons affected short-term synaptic Histidine ammonia-lyase plasticity, i.e., in the presence of the ECM, PPD seems to be much stronger than after hyaluronidase treatment, when basically no PPD was observed. A similar down-regulation of AMPAR movement during synaptic maturation was observed when studying the role of stargazin in controlling AMPAR immobilization. Interestingly, overexpression in mature neurons of mutant stargazin unable to bind their intracellular partner PSD-95 reverted to the behavior of AMPAR to ‘juvenile’ type (Bats et al., 2007). Consequently, both intracellular and ECM-derived surface compartments can influence short-term plasticity of neurons by controlling lateral diffusion and thus control the synaptic availability

of naïve AMPA receptors. It should be noted here that ECM nets are not impermeable barriers for diffusing surface proteins. They rather have to be considered as viscous structures that reduce the surface mobility of proteins. Accordingly, the size and shape of the extracellular domains of surface-exposed membrane proteins influences the mobility shift by the ECM (Frischknecht et al., 2009). Along this line, the recent characterization of the full crystal structure of AMPARs points to their very large extracellular domain, protruding over 10 nm into the extracellular space (Sobolevsky et al., 2009) and thus likely to bump into the ECM components.