Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity.

A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), maintains antidepressant-like effects in mice without adverse effects. Using brain slices from mice, researchers developed a model to study how HNK produces rapid versus sustained synaptic changes. HNK rapidly strengthened connections between neurons in the hippocampus, an effect that did not require NMDA receptor activity. However, maintaining a primed state that enhanced later long-term potentiation (a form of synaptic plasticity) did require NMDA receptors. HNK's rapid effects depended on adenylyl cyclase 1 and protein kinase A activity. The findings suggest that targeting such priming mechanisms could be a strategy for developing antidepressants.

Study at a glance

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.