Figure 1.

Schematic representation of mechanisms underlying ketamine action. Ketamine-mediated suppression of N-methyl-D-aspartate receptor (NMDA-R) activity leads to inhibition of eukaryotic elongation factor 2 (eEF2) kinase and a subsequent dephosphorylation of eEF2, with a concomitant augmentation of brain-derived neurotrophic factor (BDNF) synthesis. The depolarization from α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPA-R) activity activates voltage-dependant calcium channels (VDCCs), allowing calcium influx and exocytosis of BDNF, which can then activate TrkB receptors, in turn activating Akt and extracellular signal-regulated protein kinase (ERK). Akt and ERK activate mammalian target of rapamycin (mTOR), which enables the translation of synaptic protein by activating p70S6 kinase and inhibiting 4E binding proteins (4E-BPs). Glycogen synthase kinase-3 can be released from its inhibition of BDNF expression through phosphorylation by Akt or p70S6K. See text for additional details.