Das R6/2-Mausmodell der Chorea Huntington : verhaltensbiologische Charakteristika und der Einfluss ihres Diabetes mellitus

摘要

R6/2 transgenic mice express exon 1 of the human Huntington`s disease (HD) gene with an increased CAG repeat length and develop a progressive neurological phenotype. Some of these mice were also found to develop a diabetes mellitus. The aim of this study was to search for behavioural tests that are best applicable to monitor the behavioural abnormalities in therapy studies and to investigate the extend to which diabetes influences the disease phenotype. It was detected that the rotarod test is useful to monitor the motor coordination in transgenic mice. An accelerating rotarod paradigm was superior over testing with a rotarod at various fixed speeds since it leads to similar results with less repetitive daily trials so that exhaustion cannot contribute substantially to their decline in performance. The spontaneous explorative behaviour was monitored with an open field test. Unlike littermate controls the transgenic mice exhibited at the age of 3 weeks significant hyperactivity and after 6 weeks of age they showed a decreasing spontaneous explorative behaviour. With the morris watermaze it was possible to monitor successful cognitive decline in the first weeks of the disease. The first behavioural abnormalities in transgenic mice are shown at three weeks of age in hyperactivity in the spontaneous explorative behaviour. Afterwards a progressive decline in cognitive function parallel to motor function begins similar as in human HD. A latent diabetes mellitus was found in all transgenic mice at 9 weeks of age demonstrated by a pathological glucose tolerance test. Only 26% of the mice developed manifest diabetes. R6/2 mice with manifest diabetes showed no significant differences in survival, weight loss and motor coordination. These results suggest that diabetes mellitus is not a major contributing factor to the disease phenotype. With the present behavioural tests the main symptoms of human HD can be monitored reliable in the R6/2 animal model so that the evaluation of therapeutic studies may be possible.