We have used the R6/2 mice to study cortico-striatal glutamatergic transmission by microdialysis in freely moving mice. Basal extracellular striatal glutamate concentrations were lower in R6/2 mice at 12 weeks of age, but not at 6 weeks of age, when neurological symptoms start to develop. In contrast, K-induced glutamate release was blunted in the striatum of R6/2 mice at both 6 and 12 weeks of age as compared with age-matched controls. We also found a substantial reduction in striatal pro-BDNF (brain derived neurotrophic factor) levels associated with no changes in the mature form of BDNF, as assessed by immunoblotting, in 12-week-old R6/2 mice, suggesting a reduced turnover rate of BDNF in the striatum of these mice. These data support the hypothesis of a cortico-striatal dysfunction in Huntington's disease.