Microglial brain-derived neurotrophic factor (BDNF) supports the behavioral and synaptogenic effects of ketamine
Samuel C. Woodburn, Alexander Kuhn, David T. Dadodsky, Etienne Mueller, Justin L. Bollinger, Rosa Maria Salazar Gonzalez, J. Elliott Robinson, Lauren Larke Vollmer, Eric S. Wohleb
bioRxiv Preprint Server May 5, 2025 preprint DOI: 10.1101/2025.05.05.652266 via bioRxiv
Summary
AI-generated from the abstractMicroglial 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.
Study at a glance
| Characteristics | Preclinical experimental study |
|---|---|
| Population | Mice with conditional BDNF depletion in microglia (Cx3cr1Cre/+:Bdnffl/fl) and genotype controls (Cx3cr1Cre/+:Bdnf+/+) |
| Intervention | ketamine |
| Duration | 24 hours after injection |
| Topics | Ketamine Neuroplasticity |
| Keywords | Microglia Brain immune cells Antidepressants Antidepressant effects Antidepressant responses |
| Key finding | Microglial BDNF is required for ketamine to increase prefrontal cortex dendritic spine density and produce full antidepressant-like behavioral effects. |
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.