Analysis of Gait Disturbances and Cerebellar Dysfunction in a Spinocerebellar Ataxia-1 Mouse Model

Spinocerebellar Ataxia Type 1 (SCA1) is a neurodegenerative disorder characterized by progressive loss of motor coordination due to Purkinje cell degeneration in the cerebellum. SCA1 is characterized by CAG repeat expansion in the ataxin-1 gene, leading to protein aggregation and neuronal damage. This research investigated the effects of the SCA1 mutation on motor function and cerebellar activity in heterozygous (HET) and wild-type (WT) mice using DigiGait analysis and cerebellar electrophysiological recordings. Gait metrics, including stride length, gait speed, and stance duration, were measured weekly from 7 to 42 weeks using the DigiGait apparatus. Significant gait disturbances were observed in HET mice, with a notable decline in gait speed starting at weeks 15-16 in males and weeks 9-10 in females, as compared to the WT. There were also stride length reductions and increased stance duration, indicating a substantial motor deficit. Weekly measured weight data revealed a statistically significant difference in weight emerging by week 16 for males and week 15 for females. Electrophysiological recordings of cerebellar activity were obtained by placing electrodes in the cerebellum of mice who underwent surgery for electrode placement. Recordings focused on Purkinje cell activity. Altered firing patterns and reduced synaptic plasticity in HET mice was observed. This altered cerebellar activity correlated with the observed motor deficits, suggesting a direct relationship between Purkinje cell dysfunction and impaired gait, which has not been thoroughly investigated in existing literature. In addition to quantitative metrics, behavioral changes in HET mice were noted over time, especially with increased difficulty in running on the DigiGait apparatus. These observations underscore the progressive nature of SCA1 and its impact. Future research could explore the potential of cerebellar deep brain stimulation as a therapeutic approach to improve motor function in SCA1. Targeting Purkinje cell activity through DBS may offer a novel strategy to aid with motor deficits associated with SCA1.