Evaluation of R6/2 HD transgenic mice for therapeutic studies in Huntington's disease: behavioral testing and impact of diabetes mellitus

R6/2 transgenic mice express exon I of the human Huntington's disease (HD) gene with an increased CAG repeat length. They develop a progressive neurol ogical phenotype, die within 12-14 weeks of age and were also found to deve lop diabetes mellitus. Since R6/2 mice are broadly used to screen for poten tial therapies in HD, the aim of this study was (a) to search for behaviora l tests that are best applicable to monitor the behavioral abnormalities in therapy studies and (b) to investigate the extent to which diabetes influe nces the disease phenotype. We found that the rotarod test for motor coordi nation and the open field test for spontaneous explorative behavior were us eful to monitor the progressive behavioral deterioration of R6/2 mice. An a ccelerating rotarod paradigm was superior over testing with a rotarod at va rious fixed speeds since it leads to similar results with less repetitive d aily trials so that exhaustion cannot contribute substantially to their dec line in performance, With the Morris watermaze, however, it was only possib le to monitor cognitive decline in visuo-spatial learning in the first week s of disease since, at later stages, mice were not able to learn the task a dequately. A latent diabetes mellitus was found in all transgenic mice demo nstrated by a pathological glucose tolerance. Only 26% of the mice, however , were found to develop a manifest diabetes with increasing blood glucose l evels on normal diet over the disease period. R6/2 mice with manifest and l atent diabetes showed no significant differences in survival, weight loss, motor coordination, or spontaneous explorative behavior. These results sugg est that diabetes mellitus is not a major contributing factor to the diseas e phenotype. (C) 2001 Elsevier Science B.V. All rights reserved.