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ketamine’s dissociative side effects and abuse potential has led to the search for identification of alternative compounds that trigger rapid antidepressant effects without the psychotomimetic side effects. A successful effort will require elucidation of the molecular mechanisms that elicit the antidepressant effects of ketamine. In 2011, our group proposed a synaptic signaling pathway that can account for ketamine’s antidepressant-like effects in preclinical animal models (Autry et al, 2011). Specifically, we showed that ketamine-mediated block of resting synaptic NMDA receptor (NMDAR) activity—driven by spontaneous glutamate release—leads to deactivation of eEF2 kinase resulting in dephosphorylation of its sole known target eEF2. The dephosphorylation of eEF2 results in desuppresion of dendritic protein translation and a rapid subsequent increase in brain-derived neurotrophic factor (BDNF) expression. Released BDNF activates TrkB receptors and triggers a subsequent potentiation of AMPA receptor (AMPAR)-mediated synaptic transmission in the hippocampus, providing a synaptic basis for the antidepressant effects of ketamine (Autry et al, 2011; Nosyreva et al, 2013). Consistent with the premise, ketamine’s antidepressant effects have previously been shown to require AMPARs as NBQX, an AMPAR antagonist, attenuates the antidepressant effects in rodents (Maeng et al, 2008; Autry et al, 2011). Importantly, the model we proposed can account for the ineffectiveness of the NMDAR blocker memantine as an antidepressant in the clinic, as memantine—unlike ketamine—has a limited ability to block resting NMDAR function. However, a recent study challenged a key component of the model by suggesting that ketamine’s antidepressant action is mediated by its metabolite 2R,6R-hydroxynorketamine (2R,6R-HNK), via the same signaling pathway and AMPARmediated synaptic potentiation as outline above (Autry et al, 2011) but in a NMDAR-independent manner (Zanos et al, 2016). Validation of the same signaling pathway and effects on AMPAR-mediated potentiation—sans NMDAR block—prompted us to investigate the impact of 2R,6R-HNK on NMDAR-mediated neurotransmission. In recent experiments, we showed that 2R,6R-HNK can swiftly inhibit NMDAR transmission up to 50% at concentrations needed to trigger the intracellular signaling pathway involved in the potentiation of synaptic AMPAR responses, strongly supporting a role for NMDARblockade in this effect (Suzuki et al, 2017). Further characterization showed that the effect of 2R,6R-HNK on individual NMDA-mEPSCs mimicked those of ketamine, demonstrating that 2R,6R HNK —like ketamine— selectively inhibits NMDARs while they are open (Suzuki et al, 2017). Our study demonstrated that 50 μM 2R,6R-HNK blocks synaptic NMDARs and thus 2R,6R-HNK is not ‘NMDAR-independent’ in its action. Although we used a higher concentration than the 10 μM 2R,6R-HNK—suggested as the brain concentration in rodents following a behaviorally effective antidepressant dose of 10mg/kg 2R,6R-HNK (Zanos et al, 2016)—a recent study was not able to detect antidepressant effects of 10mg/kg 2R,6R-HNK in the same behavioral paradigms (Yang et al, 2017) used by Zanos and colleagues, raising questions about the dose of 2R,6R-HNK necessary to mediate antidepressant effects and the brain concentration necessary to trigger the molecular pathway. Moreover, a mechanism, other than the demonstrated NMDAR-blockade of 2R,6R-HNK, remains to be demonstrated. The selective action of 2R,6R-HNK on open NMDARS indicate its efficacy as an antidepressant will strongly depend on factors that impact synaptic NMDAR channel opening. These factors may include glutamate release-probability, subunit composition of synaptic NMDARs, as well as levels of coagonists. Future studies will need to take into account these synaptic factors to elucidate the specific circuits involved in the antidepressant action of ketamine as well as 2R,6R-HNK. Overall, our findings demonstrate a critical role of NMDAR-block-mediated signaling in triggering the antidepressant effects of ketamine and 2R,6R-HNK.