Conditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury.
Conditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury.
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运动神经元中有条件的Rac1敲除可恢复脊髓损伤后H反射率依赖性抑郁症。
DOI：
10.1038/s41598-021-87476-5
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发表时间：
2021-04-09
影响因子：
4.6
通讯作者：
Tan AM
中科院分区：
文献类型：
--
作者：
Benson CA;Olson KL;Patwa S;Reimer ML;Bangalore L;Hill M;Waxman SG;Tan AM
脊髓损伤(SCI)的一个主要并发症是痉挛的发展，这是一种脊髓H反射通路过度兴奋的临床症状。我们以前已经证明了树突棘发育不全与中枢神经系统损伤或疾病侮辱后的过度兴奋性障碍相关的常见结构主题。在这里，我们使用腺相关病毒(AAV)介导的Cre-Lox系统来敲除脊髓损伤后运动神经元中rac1蛋白的表达。将AAV9-Cre基因导入rac1基因修饰的成年小鼠的比目鱼肌/腓肠肌逆行感染脊髓α运动神经元三周后，我们观察到脊髓损伤动物RDD显著恢复，H反射兴奋性降低。此外，病毒介导的rac1基因敲除减少了运动神经元上树突棘发育不良的存在。在没有rac1基因敲除的对照脊髓损伤动物中，我们继续观察到与过度兴奋障碍相关的异常树突棘形态，包括成熟的蘑菇状树突棘的增加，以及整体脊柱长度和脊柱头部大小的增加。综上所述，我们的结果表明，病毒介导的腹角运动神经元rac1表达的中断可以减轻树突棘形态与神经元过度兴奋性的相关性，并逆转与脊髓损伤后痉挛相关的反射亢进。最后，我们的发现提供了运动神经元树突棘发育不良和脊髓损伤所致痉挛之间可能的机制关系的证据。
A major complication with spinal cord injury (SCI) is the development of spasticity, a clinical symptom of hyperexcitability within the spinal H-reflex pathway. We have previously demonstrated a common structural motif of dendritic spine dysgenesis associated with hyperexcitability disorders after injury or disease insults to the CNS. Here, we used an adeno-associated viral (AAV)-mediated Cre-Lox system to knockout Rac1 protein expression in motor neurons after SCI. Three weeks after AAV9-Cre delivery into the soleus/gastrocnemius of Rac1-“floxed” adult mice to retrogradely infect spinal alpha-motor neurons, we observed significant restoration of RDD and reduced H-reflex excitability in SCI animals. Additionally, viral-mediated Rac1 knockdown reduced presence of dendritic spine dysgenesis on motor neurons. In control SCI animals without Rac1 knockout, we continued to observe abnormal dendritic spine morphology associated with hyperexcitability disorder, including an increase in mature, mushroom dendritic spines, and an increase in overall spine length and spine head size. Taken together, our results demonstrate that viral-mediated disruption of Rac1 expression in ventral horn motor neurons can mitigate dendritic spine morphological correlates of neuronal hyperexcitability, and reverse hyperreflexia associated with spasticity after SCI. Finally, our findings provide evidence of a putative mechanistic relationship between motor neuron dendritic spine dysgenesis and SCI-induced spasticity.
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影响因子：
16.2
作者：
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