Major depressive disorder, characterized by aberrant glutamatergic signaling in the prefrontal cortex (PFC), is a leading cause of disability worldwide. Depression is highly comorbid with metabolic disorders, but a mechanistic link is elusive. In this issue of the JCI, Fan and coauthors report that elevated posttranslational modification with the glucose metabolite N-acetylglucosamine (GlcNAc) by O-GlcNAc transferase (OGT) contributed to stress-induced establishment of depression-like behaviors in mice. This effect was specific to medial PFC (mPFC) astrocytes, with glutamate transporter-1 (GLT-1) identified as an OGT target. Specifically, O-GlcNAcylation of GLT-1 resulted in diminished glutamate clearance from excitatory synapses. Further, astrocytic OGT knockdown restored stress-induced deficits in glutamatergic signaling, promoting resilience. These findings provide a mechanistic link between metabolism and depression and have relevance for antidepressant targets.