The rotenone exposure model of Parkinson's disease induces progressive locomotor deficits in mice

Abstract

Neurodegenerative diseases remain the leading cause of physical and cognitive disability worldwide. Within this group of diseases, Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder affecting an estimated 9.4 million people worldwide in 2020. It is characterized by the selective degeneration of dopaminergic neurons (DAn) in the substantia nigra pars compacta (SNpc), increased glial activation, and inflammatory signaling. Clinical motor symptoms include resting tremor, hunched posture, difficulties initiating movement, and a short shuffling gait. Exposure to environmental neurotoxins such as pesticides can recapitulate key pathological features of PD. Among such agents is the naturally occurring pesticide, rotenone, a mitochondrial complex I uncoupler that targets DAn in the SNpc, leading to parkinsonian phenotype in rodent models. However, it remains unknown how this toxin elicits gait disturbances throughout the course of exposure. In this study, inbred C57Bl/6 mice were exposed to 2.5 mg/kg/day of rotenone or respective vehicle control for 14 days, followed by a 7 day lesioning period. Using the Noldus CatWalk XT, a high-throughput gait tracking and analysis system, alterations in gait and locomotion were examined over the course of rotenone exposure and subsequent lesioning period. The resulting data demonstrates that rotenone exposure alters locomotion by decreasing stride lengths and speed of movements both in individual paws and with the animal's gait as a whole. The exposure induced changes in animals that progressed even after the cessation of exposure. This suggests that rotenone-induced neurotoxicity causes a sustained response in the brain leading to progressive neurologic and motor dysfunction, similar to that observed in patients with idiopathic PD.