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Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity

Neuropsychopharmacology volume 50, pages 928–940 (2025)Cite this article

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Abstract

The pharmacologically active (R,S)-ketamine (ketamine) metabolite (2 R,6 R)-hydroxynorketamine (HNK) maintains ketamine’s preclinical antidepressant profile without adverse effects. While hypotheses have been proposed to explain how ketamine and its metabolites initiate their antidepressant-relevant effects, it remains unclear how sustained therapeutic actions arise following drug elimination. To distinguish the physiological mechanisms involved in the rapid from sustained actions of HNK, we utilized extracellular electrophysiology combined with pharmacology to develop an in vitro hippocampal slice incubation model that exhibited pharmacological fidelity to the 1) rapid synaptic potentiation induced by HNK at the Schaffer collateral-CA1 (SC-CA1) synapse during bath-application to slices collected from mice, and 2) maintenance of metaplastic (priming) activity that enhanced N-methyl-D-aspartate receptor (NMDAR) activation-dependent long-term potentiation (LTP) hours after in vivo dosing. We used this model to reveal novel mechanisms engaged in HNK’s temporally-sensitive antidepressant-relevant synaptic actions, finding that the induction of synaptic potentiation by HNK did not require NMDAR activity, but NMDAR activity was necessary to maintain synaptic priming. HNK required protein kinase A (PKA) activity to rapidly potentiate SC-CA1 neurotransmission to facilitate synaptic priming that persistently promoted LTP formation. HNK’s rapid actions were blocked by inhibitors of adenylyl cyclase 1 (AC1), but not an AC5 inhibitor. We conclude that HNK rapidly potentiates SC-CA1 synaptic efficacy, which then stimulates priming mechanisms that persistently favor plasticity. Targeting such priming mechanisms may be an effective antidepressant strategy, and our incubation model may aid in revealing novel pharmacological targets.

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Fig. 1: (2R,6R)-HNK rapidly potentiates synaptic efficacy and persistently primes synaptic metaplasticity.
Fig. 2: Hippocampal slice incubation recapitulates the rapid and sustained synaptic actions of bath-applied and systemically administered (2R,6R)-HNK.
Fig. 3: Rapid potentiation of synaptic efficacy by (2R,6R)-HNK occurs independently of NMDAR activation, but persistent synaptic priming is NMDAR activation-dependent.
Fig. 4: Rapid potentiation of synaptic efficacy by (2R,6R)-HNK requires the activity of adenylyl cyclase isoform 1, but not isoform 5.
Fig. 5: (2R,6R)-HNK requires protein kinase A activity-dependent signaling to rapidly potentiate synaptic efficacy, and this potentiation facilitates persistent synaptic plasticity priming.

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The datasets produced during and/or analyzed for the present manuscript will be made available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Patrick J. Morris and Craig J. Thomas (Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD) for synthesizing and providing HNK.

Funding

Research was supported by NIH grant MH107615 and U.S. Department of Veterans Affairs Merit Awards 1I01BX006018 to TDG.

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Authors and Affiliations

  1. Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, MD, 21201, USA

    Kyle A. Brown, Musa I. Ajibola & Todd D. Gould

  2. Department of Pharmacology and Physiology, School of Medicine, University of Maryland, Baltimore, MD, 21201, USA

    Todd D. Gould

  3. Department of Neurobiology, School of Medicine, University of Maryland, Baltimore, MD, 21201, USA

    Todd D. Gould

  4. Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA

    Todd D. Gould

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KAB and TDG conceptualized the experiments conducted in the study. KAB and MIA completed the experiments and analyzed the data. KAB wrote the manuscript. All authors critically reviewed the manuscript and approved its final form.

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Correspondence to Todd D. Gould.

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Competing interests

TDG is listed as co-author in patents and patent applications related to the pharmacology and use of (2R,6R)-HNK in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. TDG has assigned his patent rights to the University of Maryland, Baltimore, but will share a percentage of any royalties that may be received by the University of Maryland, Baltimore. The contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. TDG has served as a consultant for Boehringer Ingelheim during the preceding 3 years. All other authors report no conflict of interest.

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Brown, K.A., Ajibola, M.I. & Gould, T.D. Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity. Neuropsychopharmacol. 50, 928–940 (2025). https://doi.org/10.1038/s41386-025-02085-4

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