Brain, behavior, and immunityJul 2, 2026

Microglia-produced BDNF helps ketamine improve behavior and brain cell connections

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 3, 2026

Abstract

Mice administered ketamine (10 mg/kg) exhibited increased dendritic spine density on pyramidal neurons in the prefrontal cortex.

Ketamine administration resulted in reduced immobility in the forced swim test (FST), indicating behavioral changes.
Increased dendritic spine density on pyramidal neurons in the prefrontal cortex was observed after ketamine treatment.
Changes in microglial morphology included reduced ramification in the prefrontal cortex following ketamine administration.
Increased expression of brain-derived neurotrophic factor (BDNF) was noted in isolated prefrontal cortex microglia after ketamine treatment.
Mice lacking microglial BDNF showed decreased levels of GluN2B in prefrontal cortex synaptosomes and reduced behavioral responses to ketamine.
No change in dendritic spine density in the prefrontal cortex was observed in mice lacking microglial BDNF after ketamine treatment.

Simplified

Ketamine promotes spine growth on the apical dendrites of pyramidal neurons in the prefrontal cortex (PFC), which are critical for its behavioral effects. Follow-up studies show that brain-derived neurotrophic factor (BDNF) signaling is critical for these effects. In this context, we sought to determine if microglial BDNF contributes to the synaptic and behavioral effects of ketamine. Thy1-GFP(M) mice were administered ketamine (10 mg/kg, i.p.) and assessed for behavior as well as dendritic spine density and microglial morphology in the PFC. Fluorescence-activated cell sorting (FACS) was used to isolate PFC microglia for gene expression analyses. Further studies used mice with depletion of microglial Bdnf (Cx3cr1^Cre/+:Bdnf^fl/fl) and genotype controls (Cx3cr1^Cre/+:Bdnf^+/+) to examine synaptosome protein levels and behavioral responses to ketamine. An AAV-PHP.eB construct was injected systemically to enable analyses of dendritic structures. As expected, mice show reduced FST immobility and increased dendritic spine density on PFC pyramidal neurons after ketamine. These effects were associated with reduced microglia ramification in the PFC and increased Bdnf expression in sorted PFC microglia. Subsequent studies revealed that Cx3cr1^Cre/+:Bdnf^fl/fl mice had decreased GluN2B levels in PFC synaptosomes and attenuated behavioral responses following ketamine administration. Consistent with this, we found that Cx3cr1^Cre/+:Bdnf^fl/fl mice show no change in dendritic spine density in the PFC following ketamine. These results implicate microglia in the neurobiological and behavioral effects of ketamine, and highlights the neurotrophic capacity of microglia.

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Microglia-produced BDNF helps ketamine improve behavior and brain cell connections

Abstract

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