A new mouse model for the trisomy of the Abcg1–U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome

Abstract

Mental retardation in Down syndrome (DS), the most frequent trisomy in humans, varies from moderate to severe. Several studies both in human and based on mouse models identified some regions of human chromosome 21 (Hsa21) as linked to cognitive deficits. However, other intervals such as the telomeric region of Hsa21 may contribute to the DS phenotype but their role has not yet been investigated in detail. Here we show that the trisomy of the 12 genes, found in the 0.59 Mb (Abcg1–U2af1) Hsa21 sub-telomeric region, in mice (Ts1Yah) produced defects in novel object recognition, open-field and Y-maze tests, similar to other DS models, but induces an improvement of the hippocampal-dependent spatial memory in the Morris water maze along with enhanced and longer lasting long-term potentiation in vivo in the hippocampus. Overall, we demonstrate the contribution of the Abcg1–U2af1 genetic region to cognitive defect in working and short-term recognition memory in DS models. Increase in copy number of the Abcg1–U2af1 interval leads to an unexpected gain of cognitive function in spatial learning. Expression analysis pinpoints several genes, such as Ndufv3, Wdr4, Pknox1 and Cbs, as candidates whose overexpression in the hippocampus might facilitate learning and memory in Ts1Yah mice. Our work unravels the complexity of combinatorial genetic code modulating different aspect of mental retardation in DS patients. It establishes definitely the contribution of the Abcg1–U2af1 orthologous region to the DS etiology and suggests new modulatory pathways for learning and memory.

Size Does Not Always Matter: Ts65Dn Down Syndrome Mice Show Cerebellum-Dependent Motor Learning Deficits that Cannot Be Rescued by Postnatal SAG Treatment

“…Despite its positive impact on cerebellar neuroanatomical architecture (Roper et al, 2006;Das et al, 2013), SAG treatment failed to rescue long-term cerebellar-based learning. Our results cannot argue in favor of a positive impact of SAG-treatment on neither acquisition nor consolidation during phase-reversal learning; the outcomes of TsVeh and TsSAG mice were virtually indistinguishable, whereas they significantly diverged from those of controls.…”

“…SAG activity was established by comparison to the amount of gcp proliferation after Shh stimulation (Roper et al, 2006;Das et al, 2013). On the day of birth (P0), each pup in a litter received a subcutaneous injection of 20 l of SAG to a final dose of 20 g/g, or an equal volume of vehicle.…”

“…Reduction of granule cells in Ts65Dn is correlated with reduced mitogenic gcp in trisomic mice compared with euploid (Roper et al, 2006). Indeed, treatment of Ts65Dn mice on the day of birth with the "small agonist of hedgehog pathway 1.1" (SAG) has been shown to restore granule cell precursor mitogenesis and normalize cerebellar morphology in adults (Roper et al, 2006;Das et al, 2013). However, because no consistent, cerebellum-specific functional effect has been documented in Ts65Dn mice, it is unclear whether SAG treatment might relieve Ts65Dn animals from potential deficits in cerebellar motor coordination.…”

Mouse-based genetic modeling and analysis of Down syndrome

“…The duplication mutants have been used to determine if the triplication of the entire Hsa21 syntenic regions on Mmu10, Mmu16 and/or Mmu17 as well as a sub-segment within a Hsa21 syntenic region is sufficient to cause a DS-related phenotype. [34][35][36][37][38] To determine if a given relatively small region is necessary for a phenotype, a subtractive strategy can be used by compounding a larger duplication with a deletion of the smaller sub-region. 33,[39][40][41][42] Using different combinations of Dp and Df mutants, the smallest genomic region can be identified for a specific DS phenotype.…”

“…36,72 Besides developmental cognitive deficits, other phenotypes of DS that have also been analyzed in new models include heart defects, 33,[73][74][75] Another key phenotype in DS is AD, which is early onset with AD-type neurodegeneration detected by age 40 for all the individuals carrying Ts21. 78 The neuropathological findings of AD in DS are very similar to AD without Ts21 in the pattern of emergence of specific pathological markers, which include neuritic plaques and neurofibrillary tangles.…”