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 GIAST glutamate transporters in the striatum. (C) 2009 Elsevier Inc. All rights reserved.