CYP2C19 in the developing brain of transgenic humanized knock-in mouse causes morphological changes in the cerebellum, including 11.8% atrophy

CYP2C19 is mainly, a liver enzyme that metabolizes psychotropic compounds, however, it is also expressed in the fetal brain. Transgenic knock-in mice carrying the human CYP2C19 gene show the same expression pattern of this enzyme as humans. This study aims to characterize the motor function and brain morphological phenotype of CYP2C19 transgenic mice. Experiments were performed in CYP2C19 transgenic mice with wild-type littermates as controls, in both sexes. Maximal hind paw elevation while walking was measured from video recordings of the footprint test. Structural T1-weighted MRI scans were obtained using a 9.4-T horizontal bore MRI scanner, and differences between brain region volumes were assessed using the ANCOVA, with genotype as a factor and sex as a covariate. P-values were FDR-corrected to account for multiple comparisons. Transgenic mice exhibited approximately 2-fold higher maximal hind paw elevation in adult mice (1.9-fold, [95%CI: 1.8, 2.1], p < 0.0001) compared to controls, while footprint analysis did not reveal significant differences (p> 0.1). Compared to controls, the transgenic mice showed a profound 11.8% reduction in cerebellar volume ([95%CI: -9.0-14.7%], q < 0.0001) and a moderate 4.2% reduction in hippocampal volume ([95%CI: 1.9-6.4%], q=0.015). Crus 1 region was identified as the most affected region based on the Allen Brain Atlas annotations. CYP2C19 transgenic mice exhibit a distinct motor phenotype and cerebellar atrophy, with the Crus 1 region being particularly affected. These mice are a promising animal model for the study of cerebellar development and the etiology and pathophysiology of diseases associated with cerebellar dysfunction.