Rapid and robust patterns of spontaneous locomotor deficits in mouse models of Huntington's disease

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by severe disruption of cognitive and motor functions, including changes in posture and gait. A number of HD mouse models have been engineered that display behavioral and neuropathological features of the disease, but gait alterations in these models are poorly characterized. Sensitive high-throughput tests of fine motor function and gait in mice might be informative in evaluating disease-modifying interventions. Here, we describe a hypothesis-free workflow that determines progressively changing locomotor patterns across 79 parameters in the R6/2 and Q175 mouse models of HD. R6/2 mice (120 CAG repeats) showed motor disturbances as early as at 4 weeks of age. Similar disturbances were observed in homozygous and heterozygous Q175 KI mice at 3 and 6 months of age, respectively. Interestingly, only the R6/2 mice developed forelimb ataxia. The principal components of the behavioral phenotypes produced two phenotypic scores of progressive postural instability based on kinematic parameters and trajectory waveform data, which were shared by both HD models. This approach adds to the available HD mouse model research toolbox and has a potential to facilitate the development of therapeutics for HD and other debilitating movement disorders with high unmet medical need.