Kundu Srikanya, Ghaemmaghami Javid, Sanidas Georgios, Wolff Nora, Vij Abhya, Byrd Chad, Simonti Gabriele, Triantafyllou Maria, Jablonska Beata, Dean Terry, Koutroulis Ioannis, Gallo Vittorio, Kratimenos Panagiotis
National Institutes of Health, National Center for Advancing Translational Sciences (NCATS), Bethesda, Maryland 20850.
Children's National Research Institute, Washington, DC 20012.
J Neurosci. 2025 Jan 1;45(1):e0899242024. doi: 10.1523/JNEUROSCI.0899-24.2024.
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.
新生儿缺氧（Hx）会导致白质（WM）损伤，尤其是在小脑。我们之前证明，Hx诱导的小脑浦肯野细胞（PC）活性降低会导致运动功能障碍。然而，Hx诱导的小脑WM损伤及相关运动异常的机制仍未明确。在此，我们表明小脑WM损伤及相关运动功能障碍是由PC活性驱动的，并且当PC活性恢复时会逆转。我们使用光遗传学和多电极阵列记录，操纵PC活性，并捕获WM少突胶质细胞前体细胞和GABA能中间神经元中由此产生的细胞反应。为了模拟Hx的影响，我们使用了特异性靶向正常小鼠PC层的光激活嗜盐菌视紫红质。在P13和P21抑制PC放电活动可模拟Hx中观察到的运动功能障碍。此外，对PC抑制后（P21）发育中小脑WM的组织病理学分析显示，少突胶质细胞成熟和髓鞘形成相应减少，这与我们在Hx小鼠中的发现相似。相反，PC刺激恢复了PC活性，促进了少突胶质细胞成熟，并增强了髓鞘形成，从而逆转了Hx诱导的运动功能障碍。我们的研究结果突出了PC活性在新生儿损伤后小脑WM发育和运动表现中的关键作用。
