To address the significance of enhancing myelination for functional recovery after white matter injury (WMI) in preterm infants, we characterized hypomyelination associated with chronic hypoxia and identified structural and functional deficits of excitatory cortical synapses with a prolonged motor deficit. We demonstrate that genetically delaying myelination phenocopies the synaptic and functional deficits observed in mice after hypoxia, suggesting that myelination may possibly facilitate excitatory presynaptic innervation. As a gain-of-function experiment, we specifically ablated the muscarinic receptor 1 (M1R), a negative regulator of oligodendrocyte differentiation in oligodendrocyte precursor cells. Genetically enhancing oligodendrocyte differentiation and myelination rescued the synaptic loss after chronic hypoxia and promoted functional recovery. As a proof of concept, drug-based myelination therapies also resulted in accelerated differentiation and myelination with functional recovery after chronic hypoxia. Together, our data indicate that myelination-enhancing strategies in preterm infants may represent a promising therapeutic approach for structural/functional recovery after hypoxic WMI.

中文翻译：

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增强少突胶质细胞髓鞘拯救了慢性缺氧后的突触损失并改善了功能恢复。

为了解决早产儿白质损伤（WMI）后增强髓鞘再生对功能恢复的重要性，我们将低髓鞘化与慢性缺氧相关联，并鉴定了兴奋性皮质突触的结构和功能缺陷，并伴有长期运动缺陷。我们证明，遗传上延迟的髓鞘形成表型可在缺氧后在小鼠中观察到突触和功能缺陷，这表明髓鞘形成可能促进兴奋性突触前神经支配。作为功​​能获得性实验，我们专门消融了毒蕈碱受体1（M1R），后者是少突胶质细胞前体细胞中少突胶质细胞分化的负调节剂。遗传增强少突胶质细胞的分化和髓鞘再生可以挽救慢性缺氧后的突触损失，并促进功能恢复。作为概念的证明，基于药物的髓鞘形成疗法还导致慢性缺氧后分化和髓鞘加速，功能恢复。总之，我们的数据表明，早产儿的髓鞘增强策略可能代表了低氧WMI后结构/功能恢复的有前途的治疗方法。