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Figure 4 | Molecular Brain

Figure 4

From: Corticosteroids: way upstream

Figure 4

Working model of sequential corticosteroid influences on synaptic physiology. Corticosterone-mediated changes in synaptic transmission occur at different levels and in different sequential steps. 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. Exposure to corticosteroids (e.g. during stress) may lead to activation of ERK1/2 in the presynaptic terminal (possibly through membrane corticosteroid receptors [51]); increased glutamatergic stimulation of postsynaptic AMPA receptors results in an increase in the frequency of AMPA receptor-mediated miniature postsynaptic currents (mEPSCs). 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 [141]; 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 . Phosphorylation of nuclear corticosteroid receptors, influences their translocation to the nucleus and therefore, their transcriptional activity [32], as indicated in .

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