Ketamine promotes spine growth on the apical dendrites of pyramidal neurons in the prefrontal cortex (PFC), and brain-derived neurotrophic factor (BDNF) signaling is critical for these effects. In mice, ketamine (10 mg/kg) reduced immobility in the forced swim test and increased dendritic spine density on PFC pyramidal neurons. These effects were associated with reduced microglia ramification and increased Bdnf expression in sorted PFC microglia. Mice with microglial Bdnf depletion (Cx3cr1Cre/+:Bdnffl/fl) showed decreased GluN2B levels in PFC synaptosomes, attenuated behavioral responses, and no change in dendritic spine density after ketamine. The results implicate microglia in the neurobiological and behavioral effects of ketamine.
Microglial BDNF is necessary for ketamine to increase synaptic density in the prefrontal cortex and produce antidepressant-like behavioral effects. Ketamine injection increased BDNF expression in microglia from the prefrontal cortex. Depleting BDNF specifically from microglia reduced levels of the NMDA receptor subunit GluN2B in prefrontal synapses and weakened antidepressant-like responses to ketamine, while also preventing the increase in dendritic spine density normally caused by ketamine. These results show that microglia, not just neurons, contribute to ketamine's effects on brain connections and mood, expanding the understanding of how immune cells in the brain participate in antidepressant responses.