Enhanced ERK activity extends ketamine's antidepressant effects by augmenting synaptic plasticity

• 成果类型: Article
• 署名作者: Ma, Z. Zack; Guzikowski, Natalie J.; Kim, Ji-Woon; Kavalali, Ege T.; Monteggia, Lisa M.
• 署名单位: Vanderbilt University; Vanderbilt University; Kyung Hee University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8478
• DOI: 10.1126/science.abb6748
• 发表日期: 2025-05-08
• 页码: 646-655
• 关键词: treatment-resistant depression; oral antidepressant; DOUBLE-BLIND; in-vivo; trkb; efficacy; mechanisms; safety; dusp6

摘要

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.