Multi-influential interactions controls behaviour and cognition through a limited number of pathways in Down syndrome mouse models (Dp1Rhr)

Down syndrome (DS) is the most common genetic form of intellectual disability with additional clinical features, caused by the presence of an additional copy of human chromosome 21 (Hsa21). A few number of patients with DS features, carry partial duplication of Hsa21 and their study provided novel insights into genotype–phenotype correlations. Despite the progress of genome analysis, the rareness of patients with partial duplication, and the human genetic heterogeneity, makes difficult to achieve a more detailed phenotypic map at present. As a complementary approach, we screened the in vivo DS mouse library with highly standardized behavioural tests, magnetic resonance imaging (MRI) and digged into hippocampal gene expression to go further in dissecting the genotype–phenotype correlations and in deciphering misregulated genes, functional pathways and biological cascades in DS models. Altogether this approach bring novel insights into the field. First, we unravelled the complexity of the genetic interactions between different regions of the chromosome 21 and how they play an important role in modulating the outcome of the behavioural and molecular phenotypes. Then, in depth analysis of misregulated expressed genes involved in synaptic dysfunction highlitghed six biological cascades centered around DYRK1A, GSK3beta, NPY, RHOA, NPAS4 and the SNARE complex. Finally, we provide a novel vision of the existing altered gene-gene crosstalk and molecular mechanisms that could be at play for both the DS clinical features and the rescue mechanisms by targeting specific hubs or well connected nodes that may be central to advance in our understanding of DS and therapies development. The gene expression profile of the hippocampus of five male controls littermates and five male mutant trisomic mice from the following Down Syndrome models: Dp1Yey, Dp3Yah, Ts65Dn, Dp5Yah.Dp1Rhr (also noted Dp5/Dp1), Dp5Yah, Dp1Rhr and Tg(Dyrk1a) was analyzed using the Affymetrix GeneChip® Gene 1.0 ST Array System for Mouse We analyzed the differences in gene expression between each mutant trisomic mice model and their respective control littermates independently as they were independent experiments. The only exception is for Dp5/Dp1, Dp5Yah and Dp1Rhr, as these animals were gen-erated using the same breeding by crossing Dp5Yah/ control mice Dp1Rhr/ control mice mice they share the same control littermates and are all part of the same independent experiment. Then the differences and similarities in gene expression and functional dysregulation in all the models were assessed.