Viral-induced spinal motor neuron death is non-cell-autonomous and involves glutamate excitotoxicity
Viral-induced spinal motor neuron death is non-cell-autonomous and involves glutamate excitotoxicity
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DOI：
10.1523/jneurosci.2002-04.2004
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发表时间：
2004-08-25
影响因子：
5.3
通讯作者：
Kerr, DA
中科院分区：
文献类型：
--
作者：
Darman, J;Backovic, S;Kerr, DA
神经适应性Sindbis病毒（NSV）是一种能诱导小鼠和大鼠脊髓运动神经元死亡的嗜神经病毒。在这项研究中，我们研究了nsv诱导运动神经元死亡的机制。我们发现许多退行性脊髓运动神经元没有被非NSV直接感染，这表明发生了旁观者细胞死亡。在体外和体内实验中，阻断钙渗透性AMPA受体可减轻运动神经元的死亡，证实了无兴奋毒性机制。在体内，星形胶质细胞谷氨酸再摄取的阻断增强了nsv诱导的运动神经元的损失，这表明星形胶质细胞介导的突触周围谷氨酸的清除对于限制nsv诱导的兴奋毒性损伤是重要的。易感小鼠在NSV感染期间脊髓内星形胶质细胞谷氨酸转运明显减少，早于运动神经元损伤。相反，我们发现抵抗nsv诱导瘫痪的小鼠脊髓谷氨酸摄取增加5.6倍。同样，二甲胺四环素显著增加脊髓谷氨酸转运，并保护小鼠免受nsv诱导的运动神经元死亡。这些研究表明，NSV感染在脊髓中引发一系列事件，导致星形细胞谷氨酸转运受损，并通过钙渗透性AMPA受体介导运动神经元的兴奋毒性损伤。类似的变化可能发生在其他运动神经元疾病，如肌萎缩性侧索硬化症或西尼罗病毒引起的脊髓灰质炎，提示有一个共同的组织损伤途径。
Neuroadapted Sindbis virus (NSV) is a neurotropic virus capable of inducing the death of spinal motor neurons in mice and rats. In this study we investigated the mechanisms that underlie NSV-induced motor neuron death. We found that many degenerating spinal motor neurons were not infected directly with NSV, suggesting that bystander cell death occurs. Anexcitotoxic mechanism was confirmed when blockade of calcium-permeable AMPA receptors attenuated motor neuron death both in vitro and in vivo. Blockade of astroglial glutamate reuptake potentiated NSV-induced motor neuron loss in vivo, suggesting that astrocyte-mediated removal of perisynaptic glutamate is important in limiting NSV-induced excitotoxic injury. Astroglial glutamate transport was reduced markedly in the spinal cord during NSV infection, in advance of motor neuron injury in susceptible mice. In contrast, we found 5.6-fold elevated glutamate uptake in the spinal cords of mice resistant to NSV-induced paralysis. Likewise, minocycline markedly increased spinal cord glutamate transport and protected mice from NSV-induced motor neuron death. These studies suggest that NSV infection triggers a cascade of events in the spinal cord resulting in impaired astrocytic glutamate transport and excitotoxic injury of motor neurons mediated via calcium-permeable AMPA receptors. Similar changes may occur in other motor neuron disorders such as amyotrophic lateral sclerosis or West Nile Virus-induced poliomyelitis, suggesting a common tissue injury pathway.