Figure 9.

Schematic representation of events induced by ketamine. During neurotransmission, presynaptically released glutamate binds to both AMPA and NMDA receptors. Activation of AMPA receptors depolarizes postsynaptic membrane, driving Mg²⁺ out of the NMDA receptor pore. This allows for Ca²⁺ entry to the cell, from whence it is subsequently rapidly extruded into the synaptic cleft by high-affinity PMCA. This allows for tight control of intrasynaptic [Ca²⁺]_c rises and propagation of unaltered downstream signals (A). Blockage of NMDA receptors by ketamine induces massive Ca²⁺ influx through AMPA receptors. Ketamine also inhibits PMCA, depleting cellular Ca²⁺-clearing potency and leading to elevated [Ca²⁺]_c within the synapse. This triggers formation of NMDAR/PSD95/PMCA complexes, putatively located close to the Ca²⁺ entry sites and acting to restore resting [Ca²⁺]_c. These complexes may further recruit signaling molecules but transmission of aberrant retrograde signal leads to a long-lasting increase in presynaptic glutamate secretion facilitated by overexpression of VGLUTs. Once released, glutamate is not effectively cleared due to downregulation of glial EAAT2 in what seems to constitute another adaptive change to restore defective postsynaptic NMDA receptor-mediated signaling. The excess of glutamate in the synaptic cleft may activate extra-synaptic receptors and together with dysregulated Ca²⁺ homeostasis contribute to the propagation of abnormal signals (B).