The study investigates the rapid antidepressant effects of ketamine, an NMDA receptor antagonist, in mouse models of depression. Ketamine and other NMDAR antagonists produce fast-acting behavioral antidepressant-like effects that depend on the rapid synthesis of brain-derived neurotrophic factor (BDNF). The mechanism involves the deactivation of eukaryotic elongation factor 2 kinase (eEF2K), leading to reduced eEF2 phosphorylation and increased BDNF translation. Inhibitors of eEF2K also induce similar fast-acting behavioral antidepressant-like effects. These findings suggest that protein synthesis regulation by spontaneous neurotransmission may be a viable therapeutic target for developing faster-acting antidepressants.The study investigates the rapid antidepressant effects of ketamine, an NMDA receptor antagonist, in mouse models of depression. Ketamine and other NMDAR antagonists produce fast-acting behavioral antidepressant-like effects that depend on the rapid synthesis of brain-derived neurotrophic factor (BDNF). The mechanism involves the deactivation of eukaryotic elongation factor 2 kinase (eEF2K), leading to reduced eEF2 phosphorylation and increased BDNF translation. Inhibitors of eEF2K also induce similar fast-acting behavioral antidepressant-like effects. These findings suggest that protein synthesis regulation by spontaneous neurotransmission may be a viable therapeutic target for developing faster-acting antidepressants.