Rehabilitation Decreases Spasticity by Restoring Chloride Homeostasis through the Brain-Derived Neurotrophic Factor-KCC2 Pathway after Spinal Cord Injury
Rehabilitation Decreases Spasticity by Restoring Chloride Homeostasis through the Brain-Derived Neurotrophic Factor-KCC2 Pathway after Spinal Cord Injury
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DOI：
10.1089/neu.2019.6526
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发表时间：
2019-11-13
影响因子：
4.2
通讯作者：
Cote, Marie-Pascale
中科院分区：
文献类型：
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作者：
Beverungen, Henrike;Klaszky, Samantha Choyke;Cote, Marie-Pascale
基于活动的治疗通常被整合到康复计划中，以促进脊髓损伤（SCI）后的功能恢复。其有益效果之一是减少反射亢进和痉挛，这影响了75%的SCI人群。与目前的抗痉挛药物治疗不同，康复减轻痉挛症状，而不会引起脊髓兴奋性的主动抑制，从而避免进一步干扰运动恢复。了解基于活动的治疗如何有助于减少痉挛对于确定新的药理学靶点和优化康复计划至关重要。近年来研究表明，脊髓损伤后神经元Cl-挤压因子KCC 2表达的减少与脊髓损伤后痉挛的发生发展有关。虽然运动可以降低脊髓过度兴奋和增加KCC 2表达的腰运动神经元脊髓损伤后，因果关系仍有待建立。活动依赖性过程包括脑源性神经营养因子（BDNF）表达的增加。有趣的是，BDNF是KCC 2的调节剂，也是脊髓兴奋性的有效调节剂。因此，我们假设SCI后，KCC 2表达的活动依赖性增加：1）功能上有助于减少反射亢进，2）由BDNF调节。SCI大鼠在日常康复过程中长期接受VU 0240551（KCC 2阻断剂）或TrkB-IgG（BDNF清除剂），并在损伤后4周记录H反射的频率依赖性抑制，H反射是反射亢进的监测器。我们的研究结果表明，KCC 2的活动依赖性增加功能上有助于H反射恢复，并严重依赖于BDNF的活性。这项研究提供了一个新的视角，了解如何运动影响反射亢进，确定功能恢复的生物学基础。
Activity-based therapy is routinely integrated in rehabilitation programs to facilitate functional recovery after spinal cord injury (SCI). Among its beneficial effects is a reduction of hyperreflexia and spasticity, which affects similar to 75% of the SCI population. Unlike current anti-spastic pharmacological treatments, rehabilitation attenuates spastic symptoms without causing an active depression in spinal excitability, thus avoiding further interference with motor recovery. Understanding how activity-based therapies contribute to decrease spasticity is critical to identifying new pharmacological targets and to optimize rehabilitation programs. It was recently demonstrated that a decrease in the expression of KCC2, a neuronal Cl- extruder, contributes to the development spasticity in SCI rats. Although exercise can decrease spinal hyperexcitability and increase KCC2 expression on lumbar motoneurons after SCI, a causal effect remains to be established. Activity-dependent processes include an increase in brain-derived neurotrophic factor (BDNF) expression. Interestingly, BDNF is a regulator of KCC2 but also a potent modulator of spinal excitability. Therefore, we hypothesized that after SCI, the activity-dependent increase in KCC2 expression: 1) functionally contributes to reduce hyperreflexia, and 2) is regulated by BDNF. SCI rats chronically received VU0240551 (KCC2 blocker) or TrkB-IgG (BDNF scavenger) during the daily rehabilitation sessions and the frequency-dependent depression of the H-reflex, a monitor of hyperreflexia, was recorded 4 weeks post-injury. Our results suggest that the activity-dependent increase in KCC2 functionally contributes to H-reflex recovery and critically depends on BDNF activity. This study provides a new perspective in understanding how exercise impacts hyperreflexia by identifying the biological basis of the recovery of function.