RT Journal Article
SR Electronic
T1 Cerebellar Purkinje cell activity regulates white matter response and locomotor function after neonatal hypoxia
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP e0899242024
DO 10.1523/JNEUROSCI.0899-24.2024
A1 Kratimenos, Panagiotis
A1 Kundu, Srikanya
A1 Ghaemmaghami, Javid
A1 Sanidas, Georgios
A1 Wolff, Nora
A1 Vij, Abhya
A1 Byrd, Chad
A1 Simonti, Gabriele
A1 Triantafyllou, Maria
A1 Jablonska, Beata
A1 Dean, Terry
A1 Koutroulis, Ioannis
A1 Gallo, Vittorio
YR 2024
UL http://www.jneurosci.org/content/early/2024/10/28/JNEUROSCI.0899-24.2024.abstract
AB Neonatal hypoxia (Hx) causes white matter (WM) injury, particularly in the cerebellum. We previously demonstrated 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.Significance statement Adult survivors of prematurity often experience locomotor incoordination secondary to cerebellar dysfunction. The cerebellum develops in the last trimester of pregnancy, a period that preterm neonates miss. Here, we show how neonatal hypoxia alters the crosstalk between neurons and oligodendrocytes in the developing cerebellum. Through loss-of-function and gain-of-function experiments, we unveiled that neuronal activity drives cerebellum-associated white matter injury and locomotor dysfunction after hypoxia. Importantly, restoring neuronal activity using direct neurophysiological stimulation reversed the hypoxia-induced white matter injury and locomotor deficits. Early cerebellar neuronal stimulation could serve as a potential therapeutic intervention for locomotor dysfunction in neonates.