Humanized CYP2C19 transgenic mouse as an animal model of cerebellar ataxia

Background: Animal models are essential for understanding etiology and pathophysiology of movement disorders. Previously, we have found that mice transgenic for the human CYP2C19 gene, expressed in the liver and developing brain, exhibit altered neurodevelopment associated with impairments of their motor function and emotionality. Objectives: To characterize motoric phenotype of the CYP2C19 transgenic mice and validate its usefulness as an animal model of ataxia. Methods: The rotarod and beam-walking tests were utilized to quantify the functional alterations induced by motoric phenotype. Dopaminergic system was assessed by tyrosine hydroxylase immunohistochemistry and by chromatographic quantification of the whole-brain dopamine levels. Beam-walking test was also repeated after the treatment with the dopamine receptor antagonists, ecopipam and raclopride. The volumes of 20 brain regions in the CYP2C19 transgenic mice and controls were quantified by 9.4T gadolinium-enhanced postmortem structural neuroimaging. Results: CYP2C19 transgenic mice were found to exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips using the beam-walking test (p<0.0001, n=89); the phenotype was more pronounced in younger animals. Hyperdopaminergism was observed in the CYP2C19 mice; however, the motoric impairment was not ameliorated by dopamine receptor antagonists and there was also no midbrain dopamine neuron loss in CYP2C19 mice. However, in these mice, cerebellar volume was drastically decreased (-11.8% [95%CI: -14.7, -9.0], q<0.0001, n=59), whereas a moderate decrease in hippocampal volume was observed (-4.2% [95%CI: -6.4%, -1.9%], q=0.015, n=59). Conclusions: Humanized CYP2C19 transgenic mice exhibit altered motoric function and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.