Department of Neurology, Xiangya Hospital, National Clinical Research Center for Geriatric Disorders, and Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, 410008, China.
2 papers in the library · 216 citations · publishing 2021-2025
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.
Arketamine, the (R)-enantiomer of ketamine, produces faster and longer-lasting antidepressant-like effects than esketamine in mice subjected to chronic social defeat stress. Activating the proteins CREB and MeCP2 drives the production of brain-derived neurotrophic factor (BDNF) in microglia, the brain's immune cells. This microglia-derived BDNF strengthens excitatory synaptic transmission in the infralimbic region of the medial prefrontal cortex (mPFC). It also activates mPFC neurons that project to the nucleus accumbens (NAc) shell, a brain area involved in reward and mood. These mechanisms together underlie arketamine's antidepressant-like effects, highlighting the essential role of microglial BDNF in modulating this neural pathway.