Manesh S B, Kondiles B R, Wheeler S, Liu J, Zhang L, Chernoff C, Duncan G J, Ramer M S, Tetzlaff W
International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada.
Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada.
J Neurochem. 2025 Jan;169(1):e16220. doi: 10.1111/jnc.16220. Epub 2024 Sep 13.
The development of therapeutic strategies to reduce impairments following spinal cord injury (SCI) motivates an active area of research, because there are no effective therapies. One strategy is to address injury-induced demyelination of spared axons by promoting endogenous or exogenous remyelination. However, previously, we showed that new myelin was not necessary to regain hindlimb stepping following moderate thoracic spinal cord contusion in 3-month-old mice. The present analysis investigated two potential mechanisms by which animals can re-establish locomotion in the absence of remyelination: compensation through intact white matter and conduction through spared axons. We induced a severe contusion injury to reduce the spared white matter rim in the remyelination deficient model, with no differences in recovery between remyelination deficient animals and injured littermate controls. We investigated the nodal properties of the axons at the lesion and found that in the remyelination deficient model, axons express the Nav1.2 voltage-gated sodium channel, a sub-type not typically expressed at mature nodes of Ranvier. In a moderate contusion injury, conduction velocities through the lesions of remyelination deficient animals were similar to those in animals with the capacity to remyelinate after injury. Detailed gait analysis and kinematics reveal subtle differences between remyelination deficient animals and remyelination competent controls, but no worse deficits. It is possible that upregulation of Nav1.2 channels may contribute to establishing conduction through the lesion. This conduction could contribute to compensation and regained motor function in mouse models of SCI. Such compensatory mechanism may have implications for interpreting efficacy results for remyelinating interventions in mice and the development of therapies for improving recovery following SCI.
由于目前尚无有效的治疗方法，因此开发减轻脊髓损伤（SCI）后功能障碍的治疗策略成为一个活跃的研究领域。一种策略是通过促进内源性或外源性髓鞘再生来解决损伤诱导的残留轴突脱髓鞘问题。然而，我们之前发现，对于3个月大的小鼠，中度胸段脊髓挫伤后恢复后肢行走并不需要新的髓鞘形成。本分析研究了动物在无髓鞘再生情况下重新建立运动能力的两种潜在机制：通过完整的白质进行补偿以及通过残留轴突进行传导。我们诱导了严重的挫伤性损伤，以减少髓鞘再生缺陷模型中残留的白质边缘，结果发现髓鞘再生缺陷动物与受伤的同窝对照动物在恢复方面没有差异。我们研究了损伤部位轴突的节点特性，发现在髓鞘再生缺陷模型中，轴突表达Nav1.2电压门控钠通道，这是一种通常不在成熟的郎飞结表达的亚型。在中度挫伤性损伤中，髓鞘再生缺陷动物损伤部位的传导速度与损伤后有髓鞘再生能力的动物相似。详细的步态分析和运动学研究揭示了髓鞘再生缺陷动物与有髓鞘再生能力的对照动物之间存在细微差异，但没有更严重的功能障碍。Nav1.2通道的上调可能有助于建立通过损伤部位的传导。这种传导可能有助于脊髓损伤小鼠模型中的功能补偿和运动功能恢复。这种补偿机制可能对解释小鼠髓鞘再生干预的疗效结果以及开发改善脊髓损伤后恢复的治疗方法具有重要意义。
