Human chromosome 21 orthologous region on mouse chromosome 17 is a major determinant of down syndrome-related developmental cognitive deficits

Trisomy21(Downsyndrome,DS)is themostcommongeneticcauseofdevelopmental cognitive deficits,andthe so-called Down syndrome critical region (DSCR) has been proposed as amajor determinant of this phenotype. The regions onhuman chromosome 21 (Hsa21) are syntenically conserved on mouse chromosome 10 (Mmu10), Mmu16and Mmu17.DSCRis conserved between the Cbr1 andFam3b genes on Mmu16. Ts65Dn mice carry three copies of ~100 Hsa21 gene orthologs on Mmu16 and exhibited impairments in the Morris water maze and hippocampal long-term potentiation (LTP). Converting the Cbr1-Fam3b region back to two copies in Ts65Dn mice rescued these phenotypes. In this study, we performed similar conversion of the Cbr1-Fam3b region in Dp(16)1Yey/1 mice that is triplicated for all ~115 Hsa21 gene orthologs on Mmu16, which also resulted in the restoration of the wild-type phenotypes in the Morris water maze and hippocampal LTP. However, converting the Cbr1-Fam3b region back to two copies in a complete model, Dp(10)1Yey/1;Dp(16)1Yey/1;Dp(17)1Yey/1, failed to yield the similar phenotypic restorations. But, surprisingly, converting boththe Cbr1-Fam3b region and the Hsa21 orthologous region on Mmu17 back to two copies in the complete model did completely restore thesephenotypestothe wild-type levels.Ourresultsdemonstrated that theHsa21orthologousregiononMmu17 is a major determinant of DS-related developmental cognitive deficits. Therefore, the inclusion of the three copies of thisHsa21orthologousregion inmousemodelsisnecessary for unraveling themechanismunderlying DS-associated developmental cognitive deficits and for developing effective interventions for this clinical manifestation.