Estrada-Sánchez Ana María, Montiel Teresa, Segovia José, Massieu Lourdes
Departamento de Neurociencias Instituto de Fisiología Celular Universidad Nacional Autónoma de México D.F. CP 04510, AP 70-253, México.
Neurobiol Dis. 2009 Apr;34(1):78-86. doi: 10.1016/j.nbd.2008.12.017. Epub 2009 Jan 9.
Glutamate excitotoxicity has been implicated in the neuropathology of Huntington's disease (HD), due to the toxicity of glutamate receptor agonists on striatal medium spiny neurons (MSN), the most affected neuronal population in HD. Previous studies showed functional alterations of NMDA glutamate receptors and decreased expression of glutamate transporters in transgenic models and HD patients, suggesting the presence of excitotoxic damage. We have studied the vulnerability of the striatum to glutamate toxicity in R6/2 mice at 10 and 14 weeks of age. At 10 weeks R6/2 and wild-type mice are equally vulnerable to glutamate toxicity, while at 14 weeks transgenic mice show increased damage, as assessed by Nissl and Fluoro Jade staining. In addition, increased electrical brain activity is observed after glutamate administration in transgenic mice, as monitored electroencephalographically. According to western blot analysis, increased vulnerability to glutamate toxicity correlates with decreased levels of GLT-1 and GLAST glutamate transporters in the striatum.
由于谷氨酸受体激动剂对纹状体中等棘状神经元（MSN）具有毒性，而MSN是亨廷顿舞蹈病（HD）中受影响最严重的神经元群体，因此谷氨酸兴奋性毒性与HD的神经病理学有关。先前的研究表明，在转基因模型和HD患者中，NMDA谷氨酸受体存在功能改变，谷氨酸转运体表达降低，提示存在兴奋性毒性损伤。我们研究了10周龄和14周龄的R6/2小鼠纹状体对谷氨酸毒性的易感性。10周龄时，R6/2小鼠和野生型小鼠对谷氨酸毒性的易感性相同，而14周龄时，通过尼氏染色和荧光玉染色评估，转基因小鼠显示出更大的损伤。此外，脑电图监测显示，给转基因小鼠注射谷氨酸后，脑电活动增加。根据蛋白质印迹分析，对谷氨酸毒性易感性增加与纹状体中GLT-1和GLAST谷氨酸转运体水平降低有关。
