Longitudinal analysis of the behavioural phenotype in HdhQ92 Huntington's disease knock-in mice

Huntington's disease is caused by a single mutation resulting in an expanded polyglutamine sequence which causes the production of a mutant variant of the protein huntingtin, which is ultimately responsible for the motor, cognitive and emotional symptoms and early death of the individual. Several mouse models have been created that seek to recapitulate the features of the disease. The present study sought to characterise the Hdh(Q92) mouse line longitudinally, to determine the nature, extent and age of onset of any behavioural deficits. On each of the tests used the Hdh(Q92/Q92) mice demonstrated poorer performance than their wildtype littermates, and these performance deficits were age dependent. Of the tests applied acoustic startle and prepulse inhibition proved to be the most sensitive with differences between the mouse groups appearing ∼4 months of age, an age where grip strength differences were also found. Male Hdh(Q92/Q92) mice started losing weight relative their wildtype littermates from 10 months of age, and water maze performance began to deteriorate from 14 months. There were slight differences in rotarod ability with advancing age, with the Hdh(Q92/Q92) demonstrating greater variability in performance than their wildtype littermates. Analysis of body weight and the initial stage of the water maze procedure produced clear between group differences, whereas the grip strength, rotarod and acoustic startle tests demonstrated significance only when age was a factor in the analyses, suggesting that changes in the pattern of performance over time were responsible for the differences, rather than overall group effects per se. The results highlight the necessity for the longitudinal assessment of mouse lines to detect subtle behavioural differences experimental groups.