Spontaneous glutamate release activates mGluR signaling to drive rapid antidepressant responses

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.