Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine
Molecular Psychiatry November 24, 2021 W. Yao, Qianqian Cao, Shilin Luo et al. 208 citations
In a mouse model of depression, (R)-ketamine produces longer-lasting antidepressant effects than (S)-ketamine. The study identifies a molecular pathway in microglia—cells in the brain's medial prefrontal cortex—that mediates these effects. (R)-ketamine activates the ERK-NRBP1-CREB-BDNF signaling cascade in microglia, increasing BDNF transcription. Blocking this pathway with specific inhibitors or depleting microglia prevented (R)-ketamine's antidepressant-like effects and its ability to restore reduced dendritic spine density. These findings suggest that microglial signaling is essential for (R)-ketamine's antidepressant actions.