Ketamine rapidly alleviates symptoms of treatment-resistant major depression within hours of a single administration. While this may offer a new and promising trajectory for novel therapeutic development, rapid antidepressant mechanisms of action have proven especially enigmatic. Here, I applied an in vitro-à-in vivo approach to identify the cellular actions of (2R,6R)-hydroxynorketamine (HNK) – a secondary metabolite of ketamine that exerts rapid antidepressant-like effects sine dissociative properties and abuse potential. I found that (2R,6R)-HNK promotes a rapid potentiation of glutamate release at hippocampal Schaffer collateral synapses, an important site of antidepressant action that serves as a conduit in the regulation of mood and cognition. This potentiation proved to be a synapse-selective calcium-mediated phenomenon that involves the rapid induction of cyclic adenosine monophosphate dependent protein kinase, known to actuate vesicle-associated phosphoproteins to enhance glutamate release. These properties confer (2R,6R)-HNK with an ability to restore Schaffer collateral-dependent plasticity and cognitive function in a preclinical model of treatment-resistant major depression. My findings are the first to establish a cellular mechanism by which (2R,6R)-HNK gives rise to sustained adaptations in synaptic transmission and behavior and provides a novel framework for the development of improved therapeutic options for depression.