Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model

Down syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration, and gene expression imbalance. These alterations were usually investigated separately, and the potential rescuing effects of green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG) provided disparate results due to different experimental conditions. Since a holistic evaluation of these systems is missing, we designed a longitudinal experimental setup to follow the simultaneous development of structural, functional, molecular, and genetic alterations in the Ts65Dn mouse model. In this study, we conducted a multi-modal in vivo imaging study using microcomputed tomography (µCT), magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS) to investigate the integrated development of craniofacial shape, BMD, brain volumes, and hippocampal metabolites in wildtype and Ts65Dn mice. Additionally, we evaluated the changes in body weight and performed a battery of neurodevelopmental and adult cognitive tests to assess cognitive function from birth to adulthood throughout development. At the endpoint, we also evaluated tibia microarchitecture from ex vivo µCT scans and used RNAseq to analyze cerebellar gene expression in the same mice at eight months old.