Author:

Keywords:

Down Syndrome, Morphometrics, MRI, 1116 Medical Physiology, Anatomy & Morphology, 3208 Medical physiology

Abstract:

Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21 that leads to cognitive impairment and brain dysmorphologies. This phenotype may be due to genes located in the DS Critical Region, such as the DYRK1A gene encoding a kinase involved in neurogenesis and brain development. A potent DYRK1A kinase activity inhibitor is epigallocatechin-3-gallate (EGCG). Pharmacological treatment using this green tea flavonoid can normalize DYRK1A kinase activity in the hippocampus and improve the cognitive deficits in DS young adults and trisomic TS65Dn mice. As DYRK1A is mostly expressed during embryonic development, we hypothesize that prenatal EGCG treatment could also potentially rescue brain dysmorphologies associated with DS. To assess the normal and disease-altered brain morphological changes in DS, we bred 9 litters of Ts65Dn mice and collected in vivo MRI data from trisomic and wild type mice at postnatal days 3, 14 and 29. Half of the litters were treated with 30 mg/kg day of EGCG. We segmented the images and estimated the volume of the whole brain, the four brain ventricles and the cerebellum. We also recorded the 3D coordinates of landmarks defining the shape of the brain. Morphometric analyses, based on Principal Component analyses of the Procrustes coordinates, showed significant differences between trisomic and wild type mice. Ts65Dn mice showed marked ventriculomegaly, whereas trisomic mice treated with EGCG showed normal ventricles that were not significantly different from wild type mice. Overall, this provides evidence that prenatal EGCG treatment can rescue some brain dysmorphologies in DS mouse models.