Restoration of impaired myelination underlies the long-lasting antidepressant effects of ketamine, new research suggests. Spatial transcriptomics showed that exposure of mice to chronic social defeat stress altered the expression of several myelin-related genes in the prefrontal cortex and hippocampus. Treatment with ketamine restored the expression of these genes and promoted differentiation of oligodendrocyte precursors, thereby restoring myelination. Furthermore, reducing the expression of myelin-associated oligodendrocytic basic protein suppressed the beneficial effects of ketamine. In combination, the results imply that myelination is key to the therapeutic benefits of ketamine.