ANTIDEPRESSANTS & INTRACELLULAR SIGNALING LINKED TO BDNF



 DESCRIPTION (provided by applicant): In the previous funding period we investigated the mechanism of rapid antidepressant activity of ketamine, an ionotropic glutamatergic n-methyl-d-aspartate (NMDA) receptor antagonist. We demonstrated that Brain-derived neurotrophic factor (BDNF) is required for the fast acting antidepressant effects of ketamine as these effects are lost in forebrain specific BDNF knockout mice. We found that the antidepressant effects of ketamine require protein translation, but not transcription, resulting in increases in BDNF protein levels in the hippocampus that are important for the behavioral effect. Recent work has suggested a strong causal link between blockade of resting NMDA receptor activation and rapid increases in local dendritic protein translation. Blockade of NMDA receptor activation by spontaneous glutamate release has been shown to inactive eukaryotic elongation factor 2 kinase resulting in dephosphorylation of its only known substrate, eukaryotic elongation factor 2 (eEF2), thereby increasing protein translation of target transcripts. We showed that ketamine causes a decrease in phosphorylation of eEF2, which normally impedes translation in its phosphorylated state, suggesting translational de-repression of BDNF mRNA. Moreover, inhibitors of eEF2 kinase trigger a rapid antidepressant-like effect in mice and ketamine does not elicit an antidepressant effect in eEF2 kinase null mice. These data provide the basis for the novel hypothesis that ketamine, by blocking NMDA receptors at rest, inhibits the phosphorylation of eEF2 and augments subsequent expression of BDNF, critical determinants of ketamine-mediated antidepressant efficacy. The objective of this renewal is to delineate the role of BDNF-TrkB signaling in the hippocampus in ketamine-mediated antidepressant effects, as well as how eEF2 kinase acts as a transducer between NMDA receptor activity and BDNF regulation. Collectively, this information will provide novel information on the synaptic locus, as well as the key molecules, necessary for ketamine's rapid antidepressant effects.