Darman Jessica, Backovic Stephanie, Dike Sonny, Maragakis Nicholas J, Krishnan Chitra, Rothstein Jeffrey D, Irani David N, Kerr Douglas A
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
J Neurosci. 2004 Aug 25;24(34):7566-75. doi: 10.1523/JNEUROSCI.2002-04.2004.
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. An excitotoxic 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.
神经适应性辛德毕斯病毒（NSV）是一种嗜神经病毒，能够诱导小鼠和大鼠的脊髓运动神经元死亡。在本研究中，我们调查了NSV诱导运动神经元死亡的潜在机制。我们发现，许多退化的脊髓运动神经元并未直接感染NSV，这表明存在旁观者细胞死亡现象。当钙通透性AMPA受体的阻断在体外和体内均减弱运动神经元死亡时，证实了一种兴奋性毒性机制。星形胶质细胞谷氨酸重摄取的阻断在体内增强了NSV诱导的运动神经元损失，这表明星形胶质细胞介导的突触周围谷氨酸清除在限制NSV诱导的兴奋性毒性损伤中很重要。在易感小鼠中，NSV感染期间脊髓中的星形胶质细胞谷氨酸转运显著降低，早于运动神经元损伤。相比之下，我们发现在对NSV诱导的麻痹具有抗性的小鼠脊髓中，谷氨酸摄取升高了5.6倍。同样，米诺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感染触发了脊髓中的一系列事件，导致星形胶质细胞谷氨酸转运受损以及通过钙通透性AMPA受体介导的运动神经元兴奋性毒性损伤。类似的变化可能发生在其他运动神经元疾病中，如肌萎缩侧索硬化症或西尼罗河病毒引起的脊髓灰质炎，这表明存在共同的组织损伤途径。
