Cognition and Hippocampal Plasticity in the Mouse Is Altered by Monosomy of a Genomic Region Implicated in Down Syndrome

Abstract

Down syndrome (DS) is due to increased copy number of human chromosome 21. The contribution of different genetic regions has been tested using mouse models. As shown previously, the Abcg1-U2af1 genetic region contributes to cognitive defects in working and short-term recognition memory in Down syndrome mouse models. Here we analyzed the impact of monosomy of the same genetic interval, using a new mouse model, named Ms2Yah. We used several cognitive paradigms and did not detect defects in the object recognition or the Morris water maze tests. However, surprisingly, Ms2Yah mice displayed increased associative memory in a pure contextual fear-conditioning test and decreased social novelty interaction along with a larger long-term potentiation recorded in the CA1 area following stimulation of Schaffer collaterals. Whole-genome expression studies carried out on hippocampus showed that the transcription of only a small number of genes is affected, mainly from the genetic interval (Cbs, Rsph1, Wdr4), with a few additional ones, including the postsynaptic Gabrr2, Gabbr1, Grid2p, Park2, and Dlg1 and the components of the Ubiquitin-mediated proteolysis (Anapc1, Rnf7, Huwe1, Park2). The Abcg1–U2af1 region is undeniably encompassing dosage-sensitive genes or elements whose change in copy number directly affects learning and memory, synaptic function, and autistic related behavior.

Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination

“…We then carried out gene ontology enrichment analysis of each module to gain insight into the biological significance of these clusters of co-expressed genes ( Table S6 ). This analysis confirmed a number of cellular and molecular processes previously found to be altered in DS or mouse model brains, including cell morphogenesis (Module [M] 24; Figure S5A ), RNA processing (M31), gene transcription (M52), immune responses (M54; Figure S5B ), neuronal differentiation (M4 and M45; Figure S6A,D ), synaptic transmission and regulation (M10 and M34; Figure S6B,C ) and electron transport (M14) ( Table S6 ) (Bahn et al, 2002; Lockstone et al, 2007; Sahun et al, 2014; Yoshida et al, 2013; Zampieri et al, 2014). …”

Stem and progenitor cell dysfunction in human trisomies

“…These interesting models, which may better mimic some aspects of human DS, have so far been used mainly to model the neurocognitive and cardiac defects in DS . Details of these, and of elegant refinements to narrow down the Hsa21 regions linked to defined phenotypes, are described in several reviews and are only briefly discussed here in relation to their insight into the effects of trisomy 21 on stem/progenitor cells.…”

“…Studies in individuals with DS and in DS mouse models indicate that intellectual disability in DS is directly related to impaired development of many areas of the brain, including the cerebellum, the visual, auditory and somatosensory cortex, the motor cortex and the superior temporal gyrus . Many of the available DS mouse models recapitulate the structural and functional brain abnormalities of human DS very closely [reviewed in ]. Here, we briefly discuss recent studies which have investigated the cellular and genomic basis for these defects.…”

Cbsoverdosage is necessary and sufficient to induce cognitive phenotypes in mouse models of Down syndrome and interacts genetically withDyrk1a

“…However, models carrying trisomy of the region of Mmu17 homologous with the Hsa21, also showed learning and memory defects (21, 22) and appeared to have a major impact on DS phenotypes in mouse models (23). The Dp(17 Abcg1-Cbs )1Yah (called here Dp1Yah) mice are defective in the novel object recognition test and show a long-lasting in vivo long-term potentiation (LTP) in the hippocampus while the corresponding monosomy, Ms2Yah, have defects in social discrimination with increased in vivo LTP (24). Interestingly, as observed in the rotarod test, the locomotor phenotype of the Tc1 transchromosomic model carrying an almost complete Hsa21 is rescued when the dosage of the Abcg1-Cbs region is reduced in Tc1/Ms2Yah mice (25).…”