Bioactive ketamine metabolite exerts in vivo neuroplastogenic effects to improve hippocampal function in a treatment-resistant depression model.
Cell reports May 21, 2025 Lace M Riggs, Sage Aronson, Ta-Chung M Mou et al. 2 citations
A single dose of (2R,6R)-hydroxynorketamine (HNK), a metabolite of ketamine, rapidly strengthens weakened synapses in a rat model of treatment-resistant depression. In plasticity-deficient Wistar Kyoto rats, (2R,6R)-HNK boosted glutamatergic transmission, restored long-term potentiation (LTP), and reversed deficits in hippocampal-dependent memory. The drug selectively increased activity of CA1 pyramidal neurons during novelty exploration and restored spatial recognition memory reliant on Schaffer collateral pathways. Prior spatial learning partially blocked LTP in control rats, a pattern mirrored in LTP-impaired rats where spatial learning deficits were reversed by (2R,6R)-HNK. The findings indicate that (2R,6R)-HNK promotes adaptive synaptic changes at impaired synapses, improving cognitive function.