Effects of individual segmental trisomies of human chromosome 21 syntenic regions on hippocampal long-term potentiation and cognitive behaviors in mice

Abstract

As the genomic basis for Down syndrome (DS), human trisomy 21 is the most common genetic cause of intellectual disability in children and young people. The genomic regions on human chromosome 21 (Hsa21) are syntenic to three regions in the mouse genome, located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. Recently, we have developed three new mouse models using chromosome engineering carrying the genotypes of Dp(10)1Yey/+, Dp(16)1Yey/+, or Dp(17)1Yey/+, which harbor a duplication spanning the entire Hsa21 syntenic region on Mmu10, Mmu16, or Mmu17, respectively. In this study, we analyzed the hippocampal long-term potentiation (LTP) and cognitive behaviors of these models. Our results show that, while the genotype of Dp (17)1Yey/+ results in abnormal hippocampal LTP, the genotype of Dp(16)1Yey/+ leads to both abnormal hippocampal LTP and impaired learning/memory. Therefore, these mutant mice can serve as powerful tools for further understanding the mechanism underlying cognitively relevant phenotypes associated with DS, particularly the impacts of different syntenic regions on these phenotypes.

Differential Brain, Cognitive and Motor Profiles Associated with Partial Trisomy. Modeling Down Syndrome in Mice

“…After Pennington's seminal paper (Pennington et al 2003 )we have seen arguments on the role of the hippocampus in cognitive dysfunction in patients with TRS21 (Menghini et al 2011 ) as well as in mouse models (Smith et al 1997 ;Yu et al 2010b ). Our findings confirm the hypothesis but cast a different light on conclusions drawn.…”

Trisomic and Allelic Differences Influence Phenotypic Variability During Development of Down Syndrome Mice

“…Analyses with mouse models and partial trisomies in humans have shown that certain trisomic regions correlate with both the incidence and the severity of DS phenotypes (Richtsmeier et al 2002;Olson et al 2004bOlson et al , 2007Korbel et al 2009;Lyle et al 2009;Reynolds et al 2010;Yu et al 2010). Studies investigating the penetrance and variability in DS phenotypes have previously singled out nontrisomic genes as important factors in DS phenotypes (Epstein 2001;Kerstann et al 2004).…”

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

“…MEF were obtained from C57BL6 wild‐type and DP16 (Yu et al, 2010) mice, as described (Xu, 2005). MEF and HEK293 cells were cultured in DMEM (Gibco, Life technologies) supplemented with 10% FBS (Natocord), 1% Glutamax and nonessential amino acids (Gibco, Life technologies), in a 5% CO2 and 37°C atmosphere.…”

“…Life span extension in mCAT mice was associated with reduced cardiac pathology, decreased DNA oxidative damage, protection against age‐related insulin resistance, and improved proteostasis, underscoring the role of cumulative oxidative damage in aging associated pathologies (Lee et al, 2010; Mao et al, 2012; Treuting et al, 2008; Umanskaya et al, 2014). To further understand the role of Nrf2 stabilization in homeostasis and survival of trisomic cells, we assessed the Nrf2 signaling pathway as well as the effect of mCAT in DS human fibroblasts (HF), and mouse embryonic fibroblasts (MEF) derived from Dp16 mice, a segmentally trisomic model that reproduces several clinical phenotypes present in people with DS, including cognitive impairment (Belichenko et al, 2015; Li et al, 2007; Yu et al, 2010). We found that chronic canonical Nrf2 activation is required to prevent extensive oxidative damage and is critical for survival of both DS HF and Dp16 MEF.…”