Microglial BDNF modulates arketamine’s antidepressant-like effects through cortico-accumbal pathways

Arketamine, the (R)-enantiomer of (R,S)-ketamine, shows even greater rapid and sustained antidepressant-like effects in rodent models compared to esketamine, yet the underlying mechanisms remain unclear. In this study, we used the chronic social defeat stress (CSDS) model to investigate how arketamine exerts its antidepressant-like effects. We found that activating cAMP response element-binding protein (CREB) at S133 and methyl-CpG-binding protein 2 (MeCP2) at S421 drives the transcription of brain-derived neurotrophic factor (BDNF), contributing to arketamine's antidepressant-like effects. Furthermore, microglia-derived BDNF enhances excitatory synaptic transmission in the infralimbic (IL) region of the medial prefrontal cortex (mPFC), mediating the antidepressant-like effects of arketamine in CSDS-susceptible mice. Last, microglia-derived BDNF can activate mPFC (IL) neurons projecting to the nucleus accumbens (NAc) shell, contributing to arketamine's antidepressant-like effects. These findings highlight the essential role of microglial BDNF in modulating NAc-projecting mPFC neurons, which contribute to the antidepressant-like effects of arketamine.