Bioactive ketamine metabolite exerts in vivo neuroplastogenic effects to improve hippocampal function in a treatment-resistant depression model.

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.

Study at a glance

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.