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.