Working model of sequential corticosteroid influences on synaptic physiology. Corticosterone-mediated changes in synaptic transmission occur at different levels and in different sequential steps. ① depicts synaptic transmission under basal conditions. Neuronal excitation results in glutamate secretion from synaptic vesicles at presynaptic sites into the synaptic cleft. Glutamate binds to postsynaptic glutamate-gated ion channels (in particular, AMPA receptors), which open to permit ion fluxes (Na+ influx, K+ efflux) across the AMPA receptor, resulting in a depolarization of the postsynaptic cell. Due to a voltage-dependent Mg2+ block in its membrane domain, the NMDA receptor remains inactive under basal conditions, and is activated when a certain transmission threshold is reached. ② Exposure to corticosteroids (e.g. during stress) may lead to activation of ERK1/2 in the presynaptic terminal (possibly through membrane corticosteroid receptors ); increased glutamatergic stimulation of postsynaptic AMPA receptors results in an increase in the frequency of AMPA receptor-mediated miniature postsynaptic currents (mEPSCs). ③ Enhanced activation of AMPA receptors in the previous step further depolarizes the postsynaptic membrane and activates NMDA receptors. Activated NMDA receptors (Na+ and Ca2+ influx, K+ efflux) lead to further depolarization of the postsynaptic cell, resulting in the opening of voltage-dependent Ca2+ channels (VDCC) and high postsynaptic concentrations of Ca2+. Corticosteroids may stimulate glutamate secretion so strongly, causing glutamate "spill-over" which activates not only synaptic, but also extrasynaptic, glutamate receptors ; the latter are mainly NMDA receptors of the NR2B subtype. The increased intracellular levels of Ca2+ trigger a cascade of Ca2+-dependent signaling pathways in the postsynaptic cell, which may, in turn, induce the phosphorylation and de-phosphorylation of postsynaptic glutamatergic receptors and of nuclear corticosteroid receptors (nMR and nGR). Activation of extrasynaptic NMDA receptors is thought to trigger NR2B-dependent kinases, which might initiate trafficking of extrasynaptic NR2B receptors into the postsynaptic surface. Furthermore, Ca2+-dependent signaling pathways in the postsynaptic cell participate in the regulation of AMPA receptor trafficking to and from the synaptic surface, as indicated in ④. Phosphorylation of nuclear corticosteroid receptors, influences their translocation to the nucleus and therefore, their transcriptional activity , as indicated in ⑤.