Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington's disease phenotype in the R6/2 mouse
Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington's disease phenotype in the R6/2 mouse
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DOI：
10.1016/j.neuroscience.2008.02.004
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发表时间：
2008-04-22
期刊：
影响因子：
3.3
通讯作者：
Rebec, G. V.
中科院分区：
文献类型：
--
作者：
Miller, B. R.;Dorner, J. L.;Rebec, G. V.
纹状体负责处理行为输出的皮质信息，是亨廷顿病(HD)的关键靶点，HD是一种常染色体显性遗传性疾病，特征是认知能力下降和进行性运动控制能力丧失。越来越多的证据表明，谷氨酸摄取不足是由于主要的星形胶质谷氨酸转运体GLT1下调所致。为了验证这一假设，我们给有症状的R6/2小鼠注射了头孢曲松，这是一种已知能提高GLT1表达的β-内酰胺类抗生素(200 mg/kg，连续5天)，R6/2小鼠是一种被广泛研究的HD转基因模型。与车辆相比，头孢曲松减轻了一些HD行为体征：紧爪和抽搐减少，而在正迷宫中测量的运动灵活性和开阔场地爬升增加。对纹状体GLT1表达的评估证实了头孢曲松诱导的相对于载体的增加。为了确定行为和GLT1表达的变化是否代表纹状体谷氨酸处理的变化，对行为正常的不同组小鼠进行了无净通量微透析评估。与野生型对照相比，赋形剂治疗显示R6/2小鼠的谷氨酸摄取不足，头孢曲松逆转了这一缺陷。然而，赋形剂处理的动物在GLT1的表达上没有不同，这表明R6/2小鼠的谷氨酸摄取缺陷反映了功能障碍，而不是缺失GLT1。我们的结果表明，谷氨酸摄取受损是HD病理生理学和症状学的主要因素。此外，在有症状的HD小鼠中存在谷氨酸摄取缺陷，通过用头孢曲松上调GLT1的功能表达来逆转这种缺陷可以减弱HD的表型。(C)2008年IBRO。爱思唯尔有限公司出版。保留所有权利。
The striatum, which processes cortical information for behavioral output, is a key target of Huntington's disease (HD), an autosomal dominant condition characterized by cognitive decline and progressive loss of motor control. Increasing evidence implicates deficient glutamate uptake caused by a down-regulation of GLT1, the primary astroglial glutamate transporter. To test this hypothesis, we administered ceftriaxone, a beta-lactam antibiotic known to elevate GLT1 expression (200 mg/kg, i.p., for 5 days), to symptomatic R6/2 mice, a widely studied transgenic model of HD. Relative to vehicle, ceftriaxone attenuated several HD behavioral signs: paw clasping and twitching were reduced, while motor flexibility, as measured in a plus maze, and open-field climbing were increased. Assessment of GLT1 expression in striatum confirmed a ceftriaxone-induced increase relative to vehicle. To determine if the change in behavior and GLT1 expression represented a change in striatal glutamate handling, separate groups of behaving mice were evaluated with no-net-flux microdialysis. Vehicle treatment revealed a glutamate uptake deficit in R6/2 mice relative to wild-type controls that was reversed by ceftriaxone. Vehicle-treated animals, however, did not differ in GLT1 expression, suggesting that the glutamate uptake deficit in R6/2 mice reflects dysfunctional rather than missing GLT1. Our results indicate that impaired glutamate uptake is a major factor underlying HD pathophysiology and symptomology. The glutamate uptake deficit, moreover, is present in symptomatic HD mice and reversal of this deficit by up-regulating the functional expression of GLT1 with ceftriaxone attenuates the HD phenotype. (c) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.