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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 May 8, 2025 DOI: 10.1126/science.abb6748 (opens in new tab)

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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.

Study Year Design Participants
Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats 2020 Preclinical study
A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... 2011 Animal experimental study
Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress 2017 Preclinical animal study
Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression Susceptible mice in the social defeat stress model 2016 Animal experimental study
Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression Wistar-Kyoto (WKY) rats and Wistar control rats 2020 Preclinical study

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