Microglial brain-derived neurotrophic factor (BDNF) supports the behavioral and synaptogenic effects of ketamine
bioRxiv Preprint Server – May 05, 2025
Source: bioRxiv
Summary
Brain immune cells, called microglia, are crucial for antidepressant effects. Research shows that ketamine's rapid positive impact on mood and brain function, specifically by increasing synaptic density in the prefrontal cortex, relies on brain-derived neurotrophic factor (BDNF) produced by these microglia. When microglial BDNF was available, ketamine successfully enhanced brain connections and improved antidepressant responses. This reveals a vital role for microglia in pharmacological interventions.
Abstract
Microglia have been implicated in the pathogenesis for several psychiatric disorders, yet comparatively little is known about their role in treatments for these conditions. Prior work showed that the rapid-acting antidepressant ketamine increases synaptic density in the prefrontal cortex (PFC), and that brain-derived neurotrophic factor (BDNF) signaling is required for its synaptic and behavioral effects. These studies assumed that neurons were the primary source of BDNF, but other studies have since demonstrated that microglia can produce BDNF in the brain. Still, it remains unclear if microglial BDNF is important for the antidepressant-like effects of ketamine. Our initial studies show that the behavioral and synaptic effects of ketamine are associated with increased Bdnf expression in sorted PFC microglia 24 hours after injection. We then demonstrate that conditional BDNF depletion in microglia (Cx3cr1Cre/+:Bdnffl/fl) reduces GluN2B levels in PFC synaptoneurosomes and attenuates antidepressant-like responses following ketamine treatment compared to genotype controls (Cx3cr1Cre/+:Bdnf+/+). Consistent with this, we found that Cx3cr1Cre/+:Bdnffl/fl mice show no change in dendritic spine density in the PFC following ketamine. These results indicate that microglial BDNF is important for the effects of ketamine on brain and behavior, expanding upon the role of microglia in pharmacological interventions for psychiatric disorders.