Behavioral and Molecular Analysis of a Dyrk1a Functional Reduction in the Ts65Dn Mouse Model of Down Syndrome

Abstract

Children with Down syndrome (DS) experience learning, physical, and motor delays early in life. Overexpression of Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a gene located on human chromosome 21 (Hsa 21), is in triplicate in DS and is thought to be a contributing cause of some neurodevelopmental delays seen in DS. The Ts65Dn mouse model of DS similarly contains triplication of Dyrk1a, along with 90 other orthologous Hsa 21 genes. Ts65Dn pups have shown to have significant DYRK1A protein overexpression on postnatal day 6 (P6) in the hippocampus, cerebral cortex, and cerebellum. We hypothesize that reduction of DYRK1A prior to this timepoint of overexpression will improve neurodevelopmental phenotypes in these pups. Dyrk1a was reduced from three to two copies in Ts65Dn pups at P0 to correspond with a second trimester DYRK1A reduction in developing fetuses with DS. Physical and behavioral assessments were performed on these pups from P3-P21. Ts65Dn pups showed physical, motor, and behavioral deficits as compared to euploid pups. However, Dyrk1a reduction in Ts65Dn pups did not result in vast behavioral improvements. This may be correlated with the failure of Dyrk1a functional reduction to normalize DYRK1A protein and mRNA levels seen in the P21 hippocampus, cerebral cortex, and cerebellum of these animals. Although no overall behavioral improvements were seen in the neonatal period analyzed, improvements in phenotypes may emerge later in life, as Dyrk1a functional reduction did improve Ts65Dn male pups’ emergence of running. A combination of different overexpressed protein targets in DS or an earlier Dyrk1a reduction may be ways to better explore DYRK1A reduction effects in early life.