Psilocybin robustly enhances fear extinction in male and female mice when given acutely before testing, with effects observed at all doses tested. It also produces long-term improvements in extinction retention and suppression of fear renewal in a novel context, though these effects depend on dose. Administration before fear learning or immediately after extinction does not alter behavior, showing that concurrent extinction experience is required. Blocking the 5-HT2A receptor eliminates psilocybin's effects on extinction, extinction retention, and fear renewal, while blocking the 5-HT1A receptor only reduces the effect on fear renewal. These results indicate dose, timing, context, and serotonin receptors are critical for psilocybin's facilitation of fear extinction, supporting its potential as an adjunct to extinction-based therapy for PTSD.
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.