Recent preclinical and clinical studies demonstrate that three functionally different compounds, the NMDA receptor channel blocker ketamine, mGlu2/3 receptor antagonist LY341495, and NMDA receptor glycine site agent GLYX-13 produce rapid and long lasting antidepressant effects. Furthermore, these agents are reported to stimulate ERK and mTORC1 signaling in brain. Here we used rat primary cortical culture neurons to further examine the cellular actions of these agents. The results demonstrate that low concentrations of all three compounds rapidly increase levels of the phosphorylated and activated forms of ERK and a downstream target of mTORC1, p70S6 kinase, in a concentration and time dependent manner. In addition, each compound rapidly increases BDNF release into the culture media. Further studies demonstrate that induction of BDNF release, as well as stimulation of phospho-ERK is blocked by incubation with an AMPA receptor antagonist. The requirement for AMPA receptor stimulation suggests that the effects of these rapid agents are activity dependent. This possibility is supported by studies demonstrating that neuronal silencing, via incubation with the GABAA receptor agonist muscimol, completely blocks phospho-ERK and BDNF release by each agent. Finally, incubation with each drug for 24 h increases the number and length of neuronal branches. Together, the results demonstrate that these three different rapid acting antidepressant agents increase ERK signaling and BDNF release in an activity dependent manner that leads to increased neuronal complexity. Further studies will be required to determine the exact mechanisms underlying these effects in cultured neurons and in rodent models.
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