Enhanced ERK activity extends ketamine's antidepressant effects by augmenting synaptic plasticity.

Repeated ketamine treatment to maintain its rapid antidepressant effect can cause side effects, so extending the benefit from a single dose is an unmet need. Ketamine strengthens connections at CA3-CA1 synapses in the hippocampus, which is thought to underlie its antidepressant action. By temporarily boosting ERK activity through blocking the DUSP6 enzyme, researchers enhanced this synaptic strengthening and extended the antidepressant-like behavioral effects of a single ketamine dose in mice to up to 2 months. These effects depended on the TrkB receptor in excitatory neurons. The findings suggest that targeting downstream signaling pathways could sustain ketamine's rapid antidepressant effects without repeated dosing.

Study at a glance

Abstract

Repeated ketamine treatment to maintain a rapid antidepressant effect can lead to side effects over time, highlighting an unmet clinical need for sustaining this drug's antidepressant action from a single administration. Ketamine-induced synaptic potentiation at CA3-CA1 synapses has been proposed to be a key synaptic substrate for antidepressant action. Here, we found that ketamine-induced CA3-CA1 synaptic potentiation could be augmented by transiently increasing extracellular signal-regulated kinase (ERK) activity through pharmacological inhibition of dual-specificity phosphatases 6 (DUSP6). The antidepressant-like behavioral effects of acute ketamine treatment were extended by DUSP6 inhibition for up to 2 months. The selective deletion of tropomyosin receptor kinase B (TrkB) in excitatory neurons abolished these DUSP6 inhibition-mediated synaptic and behavioral effects. These data suggest that ketamine's rapid antidepressant effects can be sustained by selectively targeting downstream intracellular signaling.