Cerebellar Purkinje Cell Activity Regulates White Matter Response and Locomotor Function after Neonatal Hypoxia

Neonatal hypoxia (Hx) causes white matter (WM) injury, particularly in the cerebellum. We previously demonstrated that Hx-induced reduction of cerebellar Purkinje cell (PC) activity results in locomotor deficits. Yet, the mechanism of Hx-induced cerebellar WM injury and associated locomotor abnormalities remains undetermined. Here, we show that the cerebellar WM injury and linked locomotor deficits are driven by PC activity and are reversed when PC activity is restored. Using optogenetics and multielectrode array recordings, we manipulated PC activity and captured the resulting cellular responses in WM oligodendrocyte precursor cells and GABAergic interneurons. To emulate the effects of Hx, we used light-activated halorhodopsin targeted specifically to the PC layer of normal mice. Suppression of PC firing activity at P13 and P21 phenocopied the locomotor deficits observed in Hx. Moreover, histopathologic analysis of the developing cerebellar WM following PC inhibition (P21) revealed a corresponding reduction in oligodendrocyte maturation and myelination, akin to our findings in Hx mice. Conversely, PC stimulation restored PC activity, promoted oligodendrocyte maturation, and enhanced myelination, resulting in reversed Hx-induced locomotor deficits. Our findings highlight the crucial role of PC activity in cerebellar WM development and locomotor performance following neonatal injury.