A time-sensitive plasticity distinguishes the rapid and sustained synaptic actions of ketamine from its (2R,6R)-hydroxynorketamine metabolite.
Kyle A Brown, Patrick J. Morris, Craig J. Thomas, Todd D Gould
Journal of Neuroscience February 3, 2026 DOI: 10.1523/JNEUROSCI.0958-25.2026 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro electrophysiology and pharmacology study Peer reviewed |
|---|---|
| Population | Mouse hippocampal slices (male and female mice) |
| Interventions | (2R 6R)-hydroxynorketamine (2R6R) (R S)-ketamine pharmacological mTOR activation pharmacological or antibody TrkB blockade |
| Topics | Esketamine Ketamine Neuroplasticity |
| Key points | The ketamine metabolite 2R6R, but not ketamine itself, induces rapid and sustained mTOR-dependent metaplasticity at hippocampal SC-CA1 synapses in mice. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 43
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
and 38 more in the library