Molecular Strategy Extends Ketamine's Antidepressant Benefits in Mice for Up to Eight Weeks

Researchers at Vanderbilt University have discovered a promising molecular approach to prolong the antidepressant effects of ketamine in mice. The study focused on enhancing ERK pathway activation by using BCI, a compound that inhibits DUSP6. When administered alongside ketamine, BCI sustained ERK signaling, leading to lasting synaptic and behavioral improvements. Specifically, the combined treatment increased ERK phosphorylation and synaptic potentiation in the hippocampal CA1 region, which correlated with prolonged antidepressant-like behaviors observed in the mice. Notably, these behavioral effects persisted for up to eight weeks post-treatment, significantly longer than ketamine alone, which typically yields effects lasting only a few days to weeks. The study employed various assessments, including electrophysiological recordings, behavioral tests like the forced swim and novelty-suppressed feeding tests, and sophisticated microscopy to measure synaptic markers. Results indicated increased surface expression of glutamate receptor subunits (GluA1 and GluA2) and enhanced synaptogenesis, emphasizing the role of ERK-mediated synaptic plasticity in sustained antidepressant responses. These findings suggest that transient modulation of ERK signaling might be key to extending ketamine’s therapeutic effects, potentially reducing dosing frequency and side effects. Future human trials will determine if targeting DUSP6 is a safe and effective strategy for long-lasting depression treatment.