Spontaneous glutamate release activates mGluR signaling to drive rapid antidepressant responses

• 成果类型: Article
• 署名作者: McCarthy, Clara I.; Ma, Z. Zack; Monteggia, Lisa M.; Kavalali, Ege T.
• 署名单位: Vanderbilt University; Vanderbilt University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12421
• DOI: 10.1073/pnas.2510642122
• 发表日期: 2025-09-16
• 关键词: metabotropic glutamate-receptor-5 mglur5; positive allosteric modulators; receptor subtype 5; animal-model; ketamine; expression; binding; calcineurin

摘要

Major depressive disorder affects millions worldwide, yet current treatments require prolonged administration. In contrast, ketamine produces rapid antidepressant effects by blocking spontaneous N-Methyl-D-Aspartate (NMDA) receptor signaling, which lifts the suppression of protein synthesis and triggers homeostatic synaptic plasticity. Here, we identify a parallel signaling pathway involving metabotropic glutamate receptor 5 (mGluR5) that promotes rapid antidepressant-like effects. We show that enhancing the endogenous mGluR5 signaling produces synaptic potentiation in the hippocampus and triggers the rapid antidepressant effect, similar to ketamine. Importantly, blocking mGluR5 prevents ketamine's effects, revealing a synergy between the two pathways. At the cellular level, spontaneous calcium transients mediated by mGluR5 activate the phosphatase calcineurin and promote eukaryotic elongation factor 2 (eEF2) dephosphorylation, increasing BDNF translation to drive synaptic plasticity. We show that quantal glutamate release activates two spatially segregated Ca2+ signals-NMDAR-and mGluR5-driven-which exert opposing effects on protein synthesis. Together, these findings highlight mGluR5 as a promising therapeutic target for rapid antidepressant action, harnessing the complex nanoscale organization of synapses.