A time-sensitive plasticity distinguishes the rapid and sustained synaptic actions of ketamine from its (2R,6R)-hydroxynorketamine metabolite.

The antidepressant effects of ketamine arise from its metabolite (2R,6R)-hydroxynorketamine (2R6R), not from ketamine itself. In mouse hippocampal slices, 2R6R rapidly strengthens synapses and induces long-lasting metaplasticity—a form of plasticity that primes synapses for future change—whereas ketamine alone does not. This rapid and sustained plasticity requires mTOR signaling and can be mimicked by activating mTOR. The sustained phase also depends on IP3 receptors, L-type calcium channels, and delayed BDNF/TrkB signaling, but not on new protein synthesis. The findings outline a sequence of molecular events underlying 2R6R's synaptic actions, with implications for developing rapid-acting antidepressants and understanding activity-dependent plasticity.

Study at a glance

Abstract

(R,S)-ketamine (ketamine) induces rapid and sustained antidepressant-relevant neuroplastogenic effects in vivo. The metabolite (2R,6R)-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.Significance statement (R,S)-ketamine's therapeutic actions follow distinct, time-sensitive plasticity phases, yet the synaptic mechanisms that mediate these states are unclear. We delineate time-dependent processes distinguishing the hippocampal synaptic actions of (R,S)-ketamine from its metabolite (2R,6R)-hydroxynorketamine (2R6R). We find that 2R6R, but not (R,S)-ketamine alone, evokes a rapid plasticity and sustained metaplasticity in the mouse hippocampus. Mammalian target of rapamycin activity was necessary and sufficient for the rapid and sustained actions of 2R6R. IP3R, BDNF/TrkB, and L-type Ca2+ channel signaling were necessary for 2R6R's metaplasticity. These results implicate distinct synaptic mechanisms relevant for the development of novel rapid-acting antidepressants, as well as delineating synaptic mechanisms engaged by activity-dependent behavior and disorders of impaired plasticity.