A Time-Sensitive Plasticity Distinguishes the Rapid and Sustained Synaptic Actions of Ketamine from Its (2 <i>R</i> ,6 <i>R</i> )-Hydroxynorketamine Metabolite

(<i>R</i>,<i>S</i>)-Ketamine (ketamine) induces rapid and sustained antidepressant-relevant neuroplastogenic effects in vivo. The metabolite (2<i>R</i>,6<i>R</i>)-hydroxynorketamine (2R6R) forms shortly after the administration of ketamine and independently elicits rapid plasticity and sustained metaplasticity. Ketamine's therapeutic actions appear to result from distinct, time-sensitive plasticity phases, though the mechanisms that mediate these phases and whether these synaptic actions are unique to ketamine or 2R6R remain poorly understood. Here, we distinguished the synaptic actions of ketamine from its metabolites at the hippocampal Schaffer collateral→CA1 (SC→CA1) synapse. By modifying ketamine's chemical structure to hinder its metabolism to 2R6R or exposing slices to ketamine or 2R6R in vitro, we find that 2R6R, but not ketamine itself, induces rapid and sustained metaplasticity in both male and female mice. 2R6R's acute plasticity and sustained metaplasticity required mammalian target of rapamycin (mTOR)-dependent signaling, and both phases of 2R6R's synaptic effects were mimicked by pharmacological mTOR activation. Rapid, mTOR-dependent potentiation evoked by 2R6R was followed by long-lasting antidepressant-relevant behavior and metaplasticity that required activation of the inositol trisphosphate receptor. L-type Ca²⁺ channel signaling was required for only sustained synaptic actions, consistent with 2R6R's metaplasticity being activity-dependent. Pharmacological or antibody TrkB blockade after, but not before, 2R6R treatment prevented metaplastic synaptic priming, indicating a delayed contribution of BDNF/TrkB signaling. Blocking protein synthesis did not prevent 2R6R-induced metaplasticity. Our results implicate a sequence of plasticity mechanisms underlying 2R6R's synaptic actions in the hippocampus. These findings are relevant for the delineation of activity-dependent and time-sensitive synaptic mechanisms relevant to the treatment of neuropsychiatric disorders.