Effects of Dyrk1a and Kcnj6 normalization on the hippocampal transcriptome in the Dp(16)1/Yey mouse model of Down syndrome

Down syndrome (DS), the most common human chromosomal disorder, is caused by trisomy 21. Recent studies show that the trisomic genes Dyrk1a and Kcnj6 play critical causative roles in DS cognitive deficits. Interestingly, an unexpected lack of improvement of hippocampal-dependent learning and memory deficits was observed when both Dyrk1a and Kcnj6 were normalized to diploidy in the DS mouse model, Dp(16)1/Yey (Dp16). In this study, we explored the molecular mechanisms underlying this phenomenon by using whole genome-wide hippocampal transcriptome analysis. In total, 142, 142, and 112 genes were found significantly differentially expressed in the Dp16, Dp16/Dyrk1aKO (Dyrk1a normalized) and Dp16;Dyrk1aKO/Kcnj6KO (Both Dyrk1a and Kcnj6 normalized) hippocampus, respectively, compared with the WT hippocampus. The majority of the common significantly differentially expressed genes (DEGs) were trisomic genes. Dyrk1a and Kcnj6 normalization mainly altered the expression of diploid genes. Normalizing Dyrk1a in the Dp16 hippocampus caused an overall downregulation of genes, whereas further Kcnj6 normalization caused an overall upregulation of genes. Both further rescuing effects and neutralizing effects were observed in Kcnj6 and Dyrk1a double-normalized mice compared with mice with Dyrk1a normalization alone. Overall design: Four genetic groups:WT, Dp16, Dp16/D-KO and Dp16;D-KO/K-KO with 5-7 samples each group were analyzed