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The Role of Eukaryotic Elongation Factor 2 Kinase in Rapid Antidepressant Action of Ketamine

      Major depressive disorder is a devastating mental disorder. Current antidepressant medications can be effective for some patients with depression; however, these drugs exert mood-elevating effects only after prolonged administration, and a sizable fraction of the patient population fails to respond to treatment. There is an urgent need for faster-acting antidepressants with reliable treatment outcomes and sustained efficacy for individuals with depression, in particular those contemplating suicide. Recent clinical studies report that ketamine, an ionotropic glutamatergic N-methyl-D-aspartate (NMDA) receptor blocker, shows fast-acting antidepressant action, thus bringing fresh perspective into preclinical studies investigating novel antidepressant targets and treatments. Our recent studies show that the effects of ketamine are dependent on brain-derived neurotrophic factor (BDNF) and subsequent activation of the high-affinity BDNF receptor, TrkB. Our findings also suggest that the fast-acting antidepressant effects of ketamine require rapid protein translation, but not transcription, resulting in robust increases in dendritic BDNF protein levels that are important for the behavioral effect. These findings also uncover eukaryotic elongation factor 2 kinase (eEF2K), a Ca2+/calmodulin dependent serine/threonine kinase that phosphorylates eEF2 and regulates the elongation step of protein translation, as a major molecular substrate mediating the rapid antidepressant effect of ketamine. Our results show that ketamine-mediated suppression of resting NMDA receptor activity leads to inhibition of eEF2 kinase and subsequent dephosphorylation of eEF2 and augmentation of BDNF synthesis. This article outlines our recent studies on the synaptic mechanisms that underlie ketamine action, in particular the properties of eEF2K as a potential antidepressant target.

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