Chronic treatment with fluoxetine downregulates mitochondrial activity in parvalbumin interneurons of prefrontal cortex

Chronic treatment with fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI), is known to promote neural plasticity through the activation of the neurotrophic receptor TrkB. Our previous studies have highlighted the role of TrkB in parvalbumin-positive interneurons (PV-INs) in mediating plasticity-related behaviors in the visual cortex and hippocampus. However, the impact of TrkB activity on gene expression and neuronal functions in the prefrontal cortex (PFC) remains unclear. This study aimed to investigate the effects of chronic fluoxetine on PV-INs in the PFC. Using Translating Ribosome Affinity Purification (TRAP), we found that fluoxetine treatment downregulated pathways involved in mitochondrial energy production, including NADH dehydrogenase and cytochrome c activity. Upregulated genes were associated with phosphatase activity, voltage-gated potassium channels, and amino acid transmembrane transport. Analysis of mitochondrial function specific in PV-INs revealed a reduction in mitochondrial membrane potential, while non-PV-INs in the PFC exhibited increased membrane potential. These findings suggest that fluoxetine selectively inactivates PV-INs in the PFC, leading to compensatory increases in mitochondrial activity in non-PV-INs. Immunohistochemical analyses further demonstrated reduced PV expression and weakened perineuronal nets in specific PFC regions. Our results underscore the differential impact of chronic fluoxetine on gene expression and mitochondrial function in PV-INs, suggesting region-specific disinhibition and enhanced plasticity in the PFC.