Bioactive ketamine metabolite exerts in vivo neuroplastogenic effects to improve hippocampal function in a treatment-resistant depression model.
Lace M Riggs, Sage Aronson, Ta-Chung M. Mou, Edna F R Pereira, Scott M. Thompson, Todd D Gould
Cell Reports May 21, 2025 DOI: 10.1016/j.celrep.2025.115743 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Wistar Kyoto rats (model of treatment-resistant depression) |
| Interventions | (2R 6R)-hydroxynorketamine |
| Topics | Depression Neuroplasticity Esketamine Ketamine |
| Keywords | Cp: neuroscience Wistar kyoto Electrophysiology Multi-color fiber photometry Novelty recognition Rapid-acting antidepressant Memory & cognition Ketamine & psychopharmacology |
| Citations | 2 |
| Key findings | (2R,6R)-HNK restores long-term potentiation and reverses deficits in hippocampal-dependent synaptic activity and spatial recognition memory in a rat model of treatment-resistant depression. |
Abstract
An acute increase in excitatory synaptic transmission contributes to the rapid antidepressant actions of neuroplastogens, including ketamine and its bioactive metabolite, (2R,6R)-hydroxynorketamine (HNK). It is hypothesized that drug-induced metaplastic changes in synaptic strength account for therapeutically relevant behavioral adaptations in vivo. Using the plasticity-deficient Wistar Kyoto model of treatment-resistant depression, we demonstrate that (2R,6R)-HNK potentiates glutamatergic transmission, promotes synaptic strength, restores long-term potentiation (LTP), and reverses deficits in hippocampal-dependent synaptic activity and behavior. (2R,6R)-HNK selectively potentiated CA1 pyramidal neuron activity during novelty exploration and restored Schaffer collateral-dependent spatial recognition memory. Prior experience with spatial learning partially occluded LTP in control rats, an effect mimicked in LTP-impaired rats in which spatial learning deficits were reversed by (2R,6R)-HNK. These findings demonstrate that (2R,6R)-HNK exerts rapid neuroplastogenic effects in vivo, which improve cognitive function and promote adaptive changes in synaptic strength at functionally impaired synapses.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cited by 2
- Structural Neurotoxic and Neuroprotective Effects of Ketamine and Esketamine in Preclinical and Human Studies: A Systematic Review Research Square May 27, 2026
- A time-sensitive plasticity distinguishes the rapid and sustained synaptic actions of ketamine from its (2R,6R)-hydroxynorketamine metabolite. Journal of Neuroscience February 3, 2026
Cites 27
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- 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
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
and 22 more in the library