Brustovetsky Tatiana, Purl Kevin, Young Anisa, Shimizu Kazuyuki, Dubinsky Janet M
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
Exp Neurol. 2004 Oct;189(2):222-30. doi: 10.1016/j.expneurol.2004.03.021.
Since excitotoxicity is hypothesized to contribute to cell death in Huntington's disease (HD), we examined the susceptibility of striatal and hippocampal neurons to glutamate-induced cell death. Striatal cultures were more susceptible to glutamate-triggered toxicity than sister hippocampal cultures. Dose-response curves were equivalent when secondary toxicity was blocked with application of the NMDA receptor antagonist, MK801, or enhanced with the pan-specific glutamate transport blocker, TBOA, following excitotoxin removal. TBOA failed to alter the dose-response characteristics of striatal excitotoxicity, ruling out reverse operation of glutamate transporters. Striatal cultures expressed less EAAC1 and less membrane-associated EAAC1, GLT1, and GLAST than hippocampal cultures. Antisense down-regulation of EAAC1 increased the sensitivity of hippocampal cultures to glutamate, indicating that this transporter can act as an important neuroprotectant. Thus, the relative expression levels of glutamate transporters, even in parts of the brain where they are considered adequately expressed, appear to influence the sensitivities of different neuronal populations to excitotoxicity.
由于兴奋性毒性被认为与亨廷顿舞蹈症（HD）中的细胞死亡有关，我们研究了纹状体和海马神经元对谷氨酸诱导的细胞死亡的易感性。纹状体培养物比海马培养物对谷氨酸引发的毒性更敏感。当在去除兴奋性毒素后应用NMDA受体拮抗剂MK801阻断继发性毒性或用泛特异性谷氨酸转运体阻滞剂TBOA增强继发性毒性时，剂量反应曲线是相同的。TBOA未能改变纹状体兴奋性毒性的剂量反应特征，排除了谷氨酸转运体的反向运作。与海马培养物相比，纹状体培养物表达的EAAC1以及膜相关的EAAC1、GLT1和GLAST更少。EAAC1的反义下调增加了海马培养物对谷氨酸的敏感性，表明这种转运体可以作为一种重要的神经保护剂。因此，谷氨酸转运体的相对表达水平，即使在大脑中被认为表达充足的部位，似乎也会影响不同神经元群体对兴奋性毒性的敏感性。
