Longitudinal analysis of the behavioural phenotype in YAC128 (C57BL/6J) Huntington's disease transgenic mice

Abstract To determine the suitability of mouse models of disease for therapeutic trials, the models must be characterised to determine their similarity to the human condition, and utility for specific therapeutic approaches. The YAC128 mouse model of HD has been bred on to C57BL/6J background in order to provide a mouse model of the disease better suited to behavioural testing, than the visually impaired original line on the FVB background. In the present study, the C57BL/6J YAC128 mice were assessed on several behavioural tasks bi-monthly between 4 and 24 months of age. On the rotarod early and stable deficits were demonstrated in the YAC128 mice from 4 months of age indicating an early abnormality in motor coordination. Early and stable deficits were also found on the balance beam measures of latency to orientate towards the beam and time to traverse it. Measures of fore and hind limb footslips on the balance beam demonstrated early and progressive limb use deficits in the YAC128 mice. On a 3-stage Morris water maze protocol, the YAC128 mice took longer and travelled further to find the hidden platform in each of the 3 locations, indicative of a spatial learning deficit. The YAC128 mice were also less reactive to the primary startle stimuli and the effects of the prepulse which may suggest striatal dysfunction. As a measure of general well being, the body weights of the mice were recorded and demonstrated increased weight in the YAC128 mice until 14 months of age, when they became comparable to that of their wildtype littermates. The YAC128 mouse on the C57BL/6J background has an early, robust and severe behavioural phenotype that shares some similarity to human HD symptomatology.