Microglial brain-derived neurotrophic factor (BDNF) supports the behavioral and synaptogenic effects of ketamine.

Ketamine promotes spine growth on the apical dendrites of pyramidal neurons in the prefrontal cortex (PFC), and brain-derived neurotrophic factor (BDNF) signaling is critical for these effects. In mice, ketamine (10 mg/kg) reduced immobility in the forced swim test and increased dendritic spine density on PFC pyramidal neurons. These effects were associated with reduced microglia ramification and increased Bdnf expression in sorted PFC microglia. Mice with microglial Bdnf depletion (Cx3cr1Cre/+:Bdnffl/fl) showed decreased GluN2B levels in PFC synaptosomes, attenuated behavioral responses, and no change in dendritic spine density after ketamine. The results implicate microglia in the neurobiological and behavioral effects of ketamine.

Study at a glance

Abstract

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 (Cx3cr1Cre/+:Bdnffl/fl) and genotype controls (Cx3cr1Cre/+: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 Cx3cr1Cre/+:Bdnffl/fl mice had decreased GluN2B levels in PFC synaptosomes and attenuated behavioral responses following ketamine administration. Consistent with this, we found that Cx3cr1Cre/+:Bdnffl/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.