Microglial BDNF modulates arketamine's antidepressant-like effects through cortico-accumbal pathways.
Science advances – July 11, 2025
Source: PubMed
Summary
Brain cells called microglia play a surprising role in how a promising antidepressant, arketamine, works. Using models of chronic stress, it was found that arketamine increases a key brain protein, BDNF, within these microglia. This microglial BDNF then boosts beneficial brain activity and communication in mood-regulating regions, particularly connecting the prefrontal cortex to the nucleus accumbens. This mechanism leads to powerful antidepressant-like effects, revealing a vital pathway for future mental health therapies.
Abstract
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.