Enhanced ERK activity extends ketamine's antidepressant effects by augmenting synaptic plasticity.
Science (New York, N.Y.) – May 08, 2025
Source: PubMed
Summary
A single dose of ketamine can rapidly lift depression, but its effects fade quickly. Scientists discovered that boosting a specific brain protein (ERK) helps ketamine work longer by strengthening connections between brain cells. By blocking a natural brake on ERK activity, researchers extended ketamine's antidepressant effects for up to two months, potentially offering a safer way to maintain its benefits without repeated doses.
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.