, 2005). Gliagenesis and structural changes of the synapse itself and the surrounding neuropil lead to a faster rise and decay of miniature excitatory postsynaptic currents without changes in amplitude. The adult ECM as a negatively charged glue between astrocytes and neurons develops during the same time window (Bruckner et al., 2000; Carulli et al., 2006, 2007; Ishii & Maeda, 2008) and may further restrict glutamate diffusion. Sensing the distribution of activated AMPA receptors utilizing the low-affinity antagonist kynurenic acid

confirmed the more focalized activation of receptors at the postsynaptic side in mature synapses (Cathala et al., 2005). An impact of the local charge distribution on the diffusion

properties of glutamate has recently find more been demonstrated by comparing AMPA receptor current decay time constants at negative and positive membrane potential (Sylantyev et al., 2008). The authors argue that high throughput screening assay transient events of depolarization during synaptic activity cause a positive net charge within the synaptic cleft that will prolong the dwell time of the negatively charged glutamate in this compartment. GABA as an electrically neutral transmitter does not display such effects (Sylantyev et al., 2008). Thus the electro-diffusion of glutamate modulates the AMPA receptor occupation as can be observed in the decay characteristics L-gulonolactone oxidase of the current. As a negatively charged structure, the hyaluronan–CSPG-based ECM, which does not penetrate the synaptic cleft, could accelerate the dispersion of glutamate once it leaves the cleft or it could contribute to the prolongation of the dwell-time of glutamate within the synaptic cleft by hindering diffusion of glutamate out of the cleft. Whether and

how the ECM may influence the local concentration of ambient extrasynaptic glutamate is currently unknown. Another important parameter that we need to know to fully appreciate the complex scenario, the average concentration of ambient glutamate, is still a matter of debate (Bouvier et al., 1992; Herman & Jahr, 2007; Featherstone & Shippy, 2008). The origin of ambient transmitters seems to be primarily spillover from active synapses (Kullmann et al., 1999; Alle & Geiger, 2007) and release from astrocytes (Fellin et al., 2004). The concentration is regulated by the activity of transporters and extrasynaptic receptors (Danbolt, 2001; Diamond, 2001), the rate of transmitter diffusion (Kullmann et al., 1996; Rusakov & Kullmann, 1998), the temperature (Asztely et al., 1997), the geometry of the extracellular space (Savtchenko & Rusakov, 2007; Sykova & Nicholson, 2008; Scimemi & Beato, 2009) and the extent of wrapping of synapses by glial cells (Oliet et al., 2001; Cathala et al., 2005; Theodosis et al., 2008).