Oligodendrocytes control potassium accumulation in white matter and seizure susceptibility

The inwardly rectifying K⁺ channel K_ir4.1 is broadly expressed by CNS glia and deficits in K_ir4.1 lead to seizures and myelin vacuolization. However, the role of oligodendrocyte K_ir4.1 channels in controlling myelination and K⁺ clearance in white matter has not been defined. Here, we show that selective deletion of K_ir4.1 from oligodendrocyte progenitors (OPCs) or mature oligodendrocytes did not impair their development or disrupt the structure of myelin. However, mice lacking oligodendrocyte K_ir4.1 channels exhibited profound functional impairments, including slower clearance of extracellular K⁺ and delayed recovery of axons from repetitive stimulation in white matter, as well as spontaneous seizures, a lower seizure threshold, and activity-dependent motor deficits. These results indicate that K_ir4.1 channels in oligodendrocytes play an important role in extracellular K⁺ homeostasis in white matter, and that selective loss of this channel from oligodendrocytes is sufficient to impair K⁺ clearance and promote seizures.