Chronic treatment with fluoxetine regulates mitochondrial features and plasticity-associated transcriptomic pathways in parvalbumin-positive interneurons of prefrontal cortex

Chronic treatment with fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI), is known to promote neural plasticity. The role of fluoxetine in plasticity has been particularly tied to parvalbumin-positive interneurons, a key population of GABAergic neurons that regulate inhibitory tone and network stability. While our previous studies have highlighted fluoxetine-induced plasticity in the visual cortex and hippocampus, its cell-type-specific effects in the prefrontal cortex (PFC) remain unclear. This study aims to investigate the effects of chronic fluoxetine treatment on PV-positive (PV+) cells, identified using PV-IRES-Cre-driven reporter expression in the PFC. Using Translating Ribosome Affinity Purification (TRAP), we found that fluoxetine treatment altered the expression of 50 distinct biological pathways. Downregulated pathways are involved in mitochondrial ATP production, including components of the electron transport chain, and ribosomes. Upregulated pathways were associated with phosphatase activity, ion channel function, and cytoskeletal remodeling —molecules broadly implicated in synaptic signaling and plasticity-related processes. In FACS-sorted cells, mitochondrial DNA (mtDNA) expression was significantly increased in PV+ cells of the PFC, while intracellular ATP levels remained unchanged. Immunohistochemical analyses demonstrated reduced PV expression and weakened perineuronal nets in specific PFC subregions, suggesting a plasticity-permissive state in PV+ cells. TOMM22 signal intensity in PV+ cells showed a slight but significant increase in the prelimbic region, suggesting potential compensatory mitochondrial biogenesis despite transcriptomic downregulation of mitochondrial genes. Our findings reveal that chronic fluoxetine induces coordinated transcriptional, structural alterations in PV+ cells of the PFC, including shifts in mitochondrial-related gene expression and plasticity-associated pathways. These changes may contribute to region-specific shifts in cortical inhibition and plasticity, complementing previous reports of fluoxetine-mediated behavioral modulation.