Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects in patients with major depressive disorder (MDD), but the underlying mechanism remains unclear. This study shows that ketamine and other NMDA receptor antagonists induce fast-acting antidepressant-like effects in mouse models through the rapid synthesis of brain-derived neurotrophic factor (BDNF). The mechanism involves the deactivation of eukaryotic elongation factor 2 (eEF2) kinase, leading to reduced eEF2 phosphorylation and increased BDNF translation. Inhibitors of eEF2 kinase also produce fast-acting antidepressant-like effects, suggesting that protein synthesis regulation by spontaneous neurotransmission may be a viable therapeutic target for developing faster-acting antidepressants. The study demonstrates that ketamine's antidepressant effects are mediated through BDNF, as BDNF knockout mice do not exhibit the same behavioral responses. Additionally, the effects of ketamine are dependent on new protein synthesis, as shown by the use of protein synthesis inhibitors like anisomycin and RNA polymerase inhibitors like actinomycin D. These findings suggest that rapid, transient BDNF translation is required for ketamine's fast-acting and long-lasting antidepressant-like effects, while long-term effects may be due to synaptic plasticity changes initiated by transient increases in BDNF translation. The study also shows that ketamine inhibits spontaneous miniature NMDA-receptor mediated currents (NMDA-mEPSC) at rest, leading to decreased eEF2 kinase activity and permitting rapid increases in BDNF translation. This process is independent of evoked neurotransmission and requires enhanced neurotransmission following NMDAR antagonist-induced plasticity occurring at rest. The findings support the hypothesis that ketamine produces rapidly acting antidepressant-like behavioral effects through inhibition of spontaneous NMDA-mEPSCs, leading to decreased eEF2 kinase activity, thus permitting rapid increases in BDNF translation. These results suggest that eEF2K inhibitors could be potential novel treatments for MDD with rapid onset.Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects in patients with major depressive disorder (MDD), but the underlying mechanism remains unclear. This study shows that ketamine and other NMDA receptor antagonists induce fast-acting antidepressant-like effects in mouse models through the rapid synthesis of brain-derived neurotrophic factor (BDNF). The mechanism involves the deactivation of eukaryotic elongation factor 2 (eEF2) kinase, leading to reduced eEF2 phosphorylation and increased BDNF translation. Inhibitors of eEF2 kinase also produce fast-acting antidepressant-like effects, suggesting that protein synthesis regulation by spontaneous neurotransmission may be a viable therapeutic target for developing faster-acting antidepressants. The study demonstrates that ketamine's antidepressant effects are mediated through BDNF, as BDNF knockout mice do not exhibit the same behavioral responses. Additionally, the effects of ketamine are dependent on new protein synthesis, as shown by the use of protein synthesis inhibitors like anisomycin and RNA polymerase inhibitors like actinomycin D. These findings suggest that rapid, transient BDNF translation is required for ketamine's fast-acting and long-lasting antidepressant-like effects, while long-term effects may be due to synaptic plasticity changes initiated by transient increases in BDNF translation. The study also shows that ketamine inhibits spontaneous miniature NMDA-receptor mediated currents (NMDA-mEPSC) at rest, leading to decreased eEF2 kinase activity and permitting rapid increases in BDNF translation. This process is independent of evoked neurotransmission and requires enhanced neurotransmission following NMDAR antagonist-induced plasticity occurring at rest. The findings support the hypothesis that ketamine produces rapidly acting antidepressant-like behavioral effects through inhibition of spontaneous NMDA-mEPSCs, leading to decreased eEF2 kinase activity, thus permitting rapid increases in BDNF translation. These results suggest that eEF2K inhibitors could be potential novel treatments for MDD with rapid onset.