Different Purkinje cell pathologies cause specific patterns of progressive ataxia in mice

Abstract

Background Gait ataxia is one of the most common and impactful consequences of cerebellar dysfunction. Purkinje cells, the sole output neurons of the cerebellar cortex, are often involved in the underlying pathology, but their specific functions during locomotor control in health and disease remain obfuscated. Objectives We aimed to describe the effect of gradual adult-onset Purkinje cell degeneration on gaiting patterns in mice and whether two different mechanisms that both lead to Purkinje cell degeneration caused different patterns in the development of gait ataxia. Methods Using the ErasmusLadder together with a newly developed limb detection algorithm and machine learning-based classification, we subjected mice to a physically challenging locomotor task with detailed analysis of single limb parameters, intralimb coordination and whole-body movement. We tested two Purkinje cell-specific mouse models, one involving stochastic cell death due to impaired DNA repair mechanisms (Pcp2-Ercc1-/-), the other carrying the mutation that causes spinocerebellar ataxia type 1 (Pcp2-ATXN1[82Q]). Results Both mouse models showed increasingly stronger gaiting deficits, but the sequence with which gaiting parameters deteriorated depended on the specific mutation. Conclusions Our longitudinal approach revealed that gradual loss of Purkinje cell function can lead to a complex pattern of loss of function over time, and this pattern depends on the specifics of the pathological mechanisms involved. We hypothesize that this variability will also be present in disease progression in patients, and our findings will facilitate the study of therapeutic interventions in mice, as very subtle changes in locomotor abilities can be quantified by our methods.

Cerebellar Purkinje Cells Control Posture in Larval Zebrafish (Danio rerio)

“…Considerable progress has been made in recent years using new tools 8,[11][12][13][14] and new perspectives 87 to understand the cerebellar contributions to sensorimotor [41][42][43][44] and non-sensorimotor behaviors [45][46][47][48] in health and disease [49][50][51] . Underlying this considerable progress is an ever-improving ability to manipulate the cerebellum without compromising rigorous measures of behavior.…”

“…Disruptions to mature cerebellar function lead to instability, unsteady gait and a compromised sense of balance 10 . Kinematic quantification by pose estimation in rodents 11,12 has opened a window into cerebellar contributions to postural behaviors in health and disease 8,13,14 . However, terrestrial gait and locomotion is complex.…”