The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia

Abstract

Aims: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. Methods:The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride.

Individualized Pharmacotherapy Utilizing Genetic Biomarkers and Novel In Vitro Systems As Predictive Tools for Optimal Drug Development and Treatment

“…Overexpression of CYP2C19 in the foetal brain has been linked to smaller hippocampus and cerebellar size, which correlates with an increased susceptibility to depression and anxiety in adulthood. This highlights the intricate connection between CYP function, drug metabolism, and neurological outcomes, emphasizing the importance of understanding these relationships for both medical and developmental considerations (Jukic et al, 2017;Milosavljević et al, 2023). While these effects were observed in mice possessing multiple copies of CYP2C19, analogous distinctions are evident in humans, particularly between those lacking CYP2C19 and those expressing high levels in the liver (Persson et al, 2017;Jukic et al, 2017;Stingl et al, 2021).…”