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.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.