Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity.
Kyle A Brown, Musa I Ajibola, Todd D Gould
Neuropsychopharmacology May 1, 2025 DOI: 10.1038/s41386-025-02085-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study using in vitro electrophysiology Peer reviewed |
|---|---|
| Population | Mouse hippocampal slices |
| Intervention | (2R |
| Topics | Esketamine Ketamine Neuroplasticity |
| Keywords | Mental-health Pharmacology Depression-treatment Brain-research |
| Citations | 13 |
| Key findings | HNK rapidly potentiates synaptic transmission at the Schaffer collateral-CA1 synapse via PKA and AC1 activity, and sustained synaptic priming requires NMDAR activity. |
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.
Comparable studies
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| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cited by 11
- Synaptic priming: A framework for pharmacotherapy in depression. Neuron November 19, 2025
- Bioactive ketamine metabolite exerts in vivo neuroplastogenic effects to improve hippocampal function in a treatment-resistant depression model. Cell Reports May 21, 2025
- The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring. Neuropsychopharmacology February 1, 2026
- Inhibition of SERT and NMDAR synergistically confers rapid antidepressant effects of ketamine National Science Review September 5, 2025
- Enhancing plasticity to treat depression and other central nervous system diseases using event-driven pharmacology. Journal of Psychopharmacology July 13, 2026
and 6 more in the library
Cites 28
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- 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 Journal of Neuroscience April 15, 1997
- 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
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
and 23 more in the library