Oligodendrocyte-specific knockout of FPN1 affects CNS myelination defects and depression-like behavior in mice.

Trace element iron is essential for the proper functioning of oligodendrocytes. Ferroportin1 (FPN1), the only known iron-exporting protein, plays a critical role in maintaining iron homeostasis within these cells. Conditional knockout of the Ferroportin1 gene in oligodendrocytes (Fpn1Olig2-cKO) induced significant depression-like behavior in mice. Moreover, a marked decrease in myelin basic protein (MBP) expression was observed in the corpus callosum, a region enriched with oligodendrocytes. This reduction was accompanied by disrupted myelin structure and cellular hyperpolarization, potentially linked to the activation of the MAPK/ERK, AKT/JNK, and NF-κB signaling pathways triggered by elevated intracellular iron levels and oxidative stress. In vitro studies using the human oligodendrocyte cell line MO3.13 demonstrated that FPN1 silencing increased intracellular iron accumulation, leading to elevated reactive oxygen species (ROS) and activation of both MAPK/ERK and pro-inflammatory signaling pathways. Pharmacological suppression of the β-Catenin pathway using ICG-001 established NF-κB as its downstream signaling mediator. The inflammatory response in oligodendrocytes may further activate microglia and the intracellular IL-6/STAT3 pathway, resulting in upregulated hepcidin mRNA levels in the prefrontal cortex (PFC) and hippocampus. Consequently, iron deficiency in these brain regions impaired electrical conduction in mice. Additionally, impaired synaptic formation in the PFC and hippocampus contributed to the observed depression-like phenotypes in mice. This study highlights the pivotal role of FPN1 in iron efflux from oligodendrocytes. FPN1 deficiency-induced iron overload exacerbates ROS production, triggering neuroinflammation, which may potentiate microglial activation and the IL-6/STAT3 pathway. The subsequent hepcidin-mediated iron sequestration reduces iron availability in the PFC and hippocampus, ultimately disrupting synaptogenesis and neuronal excitability, and culminating in depression-like behaviors.