Compensatory changes after spinal cord injury in a remyelination deficient mouse model

IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
S. B. Manesh, B. R. Kondiles, S. Wheeler, J. Liu, L. Zhang, C. Chernoff, G. J. Duncan, M. S. Ramer, W. Tetzlaff
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Abstract

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.image
再髓鞘化缺陷小鼠模型脊髓损伤后的补偿性变化
由于目前还没有有效的疗法,因此开发治疗策略以减少脊髓损伤(SCI)后的损伤成为一个活跃的研究领域。其中一种策略是通过促进内源性或外源性再髓鞘化来解决损伤引起的幸免轴突脱髓鞘问题。然而,我们之前的研究表明,3 个月大的小鼠在中度胸脊髓挫伤后恢复后肢步态并不需要新的髓鞘。本分析研究了动物在没有髓鞘再形成的情况下重建运动的两种潜在机制:通过完整的白质进行补偿和通过幸免的轴突进行传导。我们诱导了严重的挫伤,以减少再髓鞘化缺陷模型中幸免的白质边缘,再髓鞘化缺陷动物与受伤的同窝对照组在恢复方面没有差异。我们研究了病变处轴突的结节特性,发现在再髓鞘化缺陷模型中,轴突表达Nav1.2电压门控钠通道,这种亚型通常不在成熟的Ranvier结节中表达。在中度挫伤中,通过髓鞘再形成缺陷动物病变部位的传导速度与受伤后具有髓鞘再形成能力的动物相似。详细的步态分析和运动学研究显示,再髓鞘化缺陷动物与有再髓鞘化能力的对照组之间存在细微差别,但没有更严重的缺陷。Nav1.2通道的上调可能有助于通过病变建立传导。这种传导可能有助于脊髓损伤小鼠模型的代偿和运动功能的恢复。这种代偿机制可能对解释小鼠再髓鞘化干预的疗效结果和开发改善 SCI 后恢复的疗法有影响。
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来源期刊
Journal of Neurochemistry
Journal of Neurochemistry 医学-神经科学
CiteScore
9.30
自引率
2.10%
发文量
181
审稿时长
2.2 months
期刊介绍: Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.
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