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

Abstract

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.

Global Rhes knockout in the Q175 Huntington’s disease mouse model

“…Related to these changes, back body posture was lowered in the Q175 mice, as indicated by lower tail base height, accompanied with increased hind limb protraction, seen especially at the latest time point of 12 months of age (Figs 2 and 3 and S2 Fig ). Both of these findings are in line with the previously reported findings [ 31 ]. In addition to these, height of the tail tip was lower, hind limb step width was wider (Figs 2 and 3 ), and hind limb trajectory shapes were altered in the Q175 mice, compared to WT mice.…”

“…Q175 phenotype . The Q175 mice exhibited deficits in fine motor capabilities as reported earlier [ 31 ]. In addition to the overall gait score (Figs 2 and 3 ) a varimax analysis [ 31 ] for the data, is presented in supplementary data ( S2 Fig ).…”

“…The Q175 mice exhibited deficits in fine motor capabilities as reported earlier [ 31 ]. In addition to the overall gait score (Figs 2 and 3 ) a varimax analysis [ 31 ] for the data, is presented in supplementary data ( S2 Fig ). The clearest Q175 phenotype was observed in parameters such as joint angle ranges, and especially in the parameters describing the degree of within subject variation of the joint angle ranges.…”

“…In addition to these, height of the tail tip was lower, hind limb step width was wider (Figs 2 and 3 ), and hind limb trajectory shapes were altered in the Q175 mice, compared to WT mice. A few gait features were observed in the Q175 mice in the current study that somewhat differed from those described before [ 31 ]. There were no significant differences in the movement speed or the different modes of cadence between the genotypes, both of which were significantly altered in the previous study [ 31 ].…”

“…The scores were obtained by projecting the (normalized) parameter data of each individual mouse onto the discriminant vector. Details of the fine motor kinematic analysis have been reported previously [ 31 ].…”