Multi-influential interactions alters behaviour and cognition through six main biological cascades in Down syndrome mouse models

Down syndrome (DS) is the most common genetic form of intellectual disability caused by the presence of an additional copy of human chromosome 21. To provide novel insights into genotype–phenotype correlations, we screened the DS mouse library with standardized behavioural tests, magnetic resonance imaging (MRI) and hippocampal gene expression. Altogether this approach brings novel insights into the field. First, we unravelled several genetic interactions between different regions of the chromosome 21 and how they importantly contribute in altering the outcome of the phenotypes in brain function and structure. Then, in depth analysis of misregulated expressed genes involved in synaptic dysfunction highlitghed 6 biological cascades centered around DYRK1A, GSK3β, NPY, SNARE, RHOA and NPAS4. Finally, we provide a novel vision of the existing altered gene-gene crosstalk and molecular mechanisms targeting specific hubs in DS models that should become central to advance in our understanding of DS and therapies development.