Neutralization of Inhibitory Molecule NG2 Improves Synaptic Transmission, Retrograde Transport, and Locomotor Function after Spinal Cord Injury in Adult Rats
Neutralization of Inhibitory Molecule NG2 Improves Synaptic Transmission, Retrograde Transport, and Locomotor Function after Spinal Cord Injury in Adult Rats
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DOI：
10.1523/jneurosci.4702-12.2013
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发表时间：
2013-02-27
影响因子：
5.3
通讯作者：
Arvanian, Victor L.
中科院分区：
文献类型：
--
作者：
Petrosyan, Hayk A.;Hunanyan, Arsen S.;Arvanian, Victor L.
NG 2属于硫酸软骨素蛋白多糖家族，在脊髓损伤（SCI）后表达上调，是限制SCI后纤维生长的主要抑制因子。已经报道了通过抗NG 2单克隆抗体（NG 2-Ab）中和NG 2对轴突生长的抑制作用。此外，最近的研究表明，外源性NG 2诱导轴突传导阻滞。在这项研究中，我们证明了急性脊髓内注射NG 2-Ab可以防止NG 2引起的急性传导阻滞。长期鞘内输注NG 2-Ab改善了慢性胸中部外侧半切（HX）损伤引起的以下缺陷：（1）突触传递至腰运动神经元，（2）解剖示踪剂将荧光红从L5逆行转运至L1，（3）自动步态分析评估的运动功能。我们收集的数据，试图了解的细胞和分子机制的NG 2-Ab诱导的改善突触传递在HX损伤的脊髓。这些数据表明：（1）慢性NG 2-Ab输注改善了慢性HX损伤大鼠中的传导和轴突兴奋性，（2）抗体治疗增加了脊髓节段L1-L5腹侧区域的轴突能轴突的密度，（3）并且NG 2阳性过程在节点Na+通道位置处的节点间隙内接触Ranvier节点，已知其对于动作电位沿沿着轴突的传播是关键的。总之，这些结果表明，用NG 2-Ab治疗部分改善受损脊髓中的突触和解剖可塑性，并促进HX SCI后的功能恢复。针对NG 2的中和抗体可能是促进SCI后轴突传导的一种很好的方法。
NG2belongs to the family of chondroitin sulfate proteoglycans that are upregulated after spinal cord injury (SCI) and are major inhibitory factors restricting the growth of fibers after SCI. Neutralization of NG2's inhibitory effect on axon growth by anti-NG2 monoclonal antibodies (NG2-Ab) has been reported. In addition, recent studies show that exogenous NG2 induces a block of axonal conduction. In this study, we demonstrate that acute intraspinal injections of NG2-Ab prevented an acute block of conduction by NG2. Chronic intrathecal infusion of NG2-Ab improved the following deficits induced by chronic midthoracic lateral hemisection (HX) injury: (1) synaptic transmission to lumbar motoneurons, (2) retrograde transport of fluororuby anatomical tracer from L5 to L1, and (3) locomotor function assessed by automated CatWalk gait analysis. We collected data in an attempt to understand the cellular and molecular mechanisms underlying the NG2-Ab-induced improvement of synaptic transmission in HX-injured spinal cord. These data showed the following: (1) that chronic NG2-Ab infusion improved conduction and axonal excitability in chronically HX-injured rats, (2) that antibody treatment increased the density of serotonergic axons with ventral regions of spinal segments L1-L5, (3) and that NG2-positive processes contact nodes of Ranvier within the nodal gap at the location of nodal Na+ channels, which are known to be critical for propagation of action potentials along axons. Together, these results demonstrate that treatment with NG2-Ab partially improves both synaptic and anatomical plasticity in damaged spinal cord and promotes functional recovery after HX SCI. Neutralizing antibodies against NG2 may be an excellent way to promote axonal conduction after SCI.