Enhanced ERK activity extends ketamine's antidepressant effects by augmenting synaptic plasticity.
Science (New York, N.Y.) May 8, 2025 Z Zack Ma, Natalie J Guzikowski, Ji-Woon Kim et al. 44 citations
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.