Enhanced ERK activity extends ketamine's antidepressant effects by augmenting synaptic plasticity.
Z Zack Ma, Natalie J Guzikowski, Ji-Woon Kim, Ege T Kavalali, Lisa M Monteggia
Science (New York, N.Y.) May 8, 2025 DOI: 10.1126/science.abb6748 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamine DUSP6 inhibition |
| Duration | Up to 2 months |
| Topics | Depression Esketamine Ketamine Neuroplasticity |
| Keywords | Ketamine therapy Mental health treatment Brain chemistry |
| Citations | 44 |
| Key findings | Inhibiting DUSP6 to transiently increase ERK activity extended the antidepressant-like behavioral effects of a single ketamine dose in mice for up to 2 months, an effect dependent on TrkB in excitatory neurons. |
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.