In healthy individuals and stress-resilient mice, astrocytes remove glutamate from synapses via GLT-1 to regulate glutamatergic neurotransmission. Importantly, this glutamate is converted to glutamine and shuttled back to neurons for reconversion to glutamate, thereby ensuring a continual supply of this essential neurotransmitter. Fan et al. (25) show that in men with depression and stress-susceptible male mice, OGT levels are increased in the PFC, a brain area involved in executive functions, social interactions, and mood regulation. This change is specific to astrocytes where the OGT enzyme catalyzes O-GlcNAcylation of GLT-1, modulating glutamate transport at the tripartite synapse. An elevated rate of this OGT-mediated posttranslational modification inhibits GLT-1 activity, leading to an increase in glutamate level in the synaptic cleft in the short-term, while simultaneously limiting transfer of glutamine to neurons and possibly reducing long-term glutamate availability. The resulting aberrant glutamatergic signaling causes reductions in dendrite complexity and depression-like symptoms, including social avoidance.