Functional Analysis of Genes Implicated in Down Syndrome: 1. Cognitive Abilities in Mice Transpolygenic for Down Syndrome Chromosomal Region-1 (DCR-1)

Abstract

Down syndrome occurs every 1/1000 births and is the most frequent genetic cause of mental retardation. The genetic substrate of Down syndrome, an extra chromosome 21, was discovered by Lejeune, half-a-century ago, and the chromosome has been fully sequenced, although the gene(s) implicated in the mental retardation observed with the syndrome are still unknown. Observations of patients with partial trisomy of the 21q22.2 fragment suggest that most of the signs of the syndrome, including mental retardation, could be influenced by the region referred to as the Down Minimal Chromosomal Region-1 (DCR-1) for that reason. Using the extensive syntenies between human chromosome 21 and murine chromosome 16, Smith et al. (1995, 1997) developed transpolygenic mice with human chromosome 21 fragments covering the DCR-1. Here, we explored cognitive performances in mice over-expressing the genes carried by these fragments with the Morris water-maze and fear-conditioning procedures. The 152F7 transpolygenic mice had lower performance levels, compared to non-transgenic and other transgenic mice on most measurements in the water-maze. In fear-conditioning, all transgenic mice recorded lower performance levels compared to controls in the altered context stage. The 230E8, 141G6 and 285E6 mice failed to learn or react when the sound used as the conditional stimulus was added. These results showed that the 152F7 region played a crucial role in cognitive impairment, supporting the hypothesis of DYRK-1A gene involvement. However, the data presented here also suggest that other chromosomal regions within the DCR-1 may be involved in specific cognitive functions.

Trisomy of the G protein-coupled K+channel gene,Kcnj6, affects reward mechanisms, cognitive functions, and synaptic plasticity in mice

“…Alternatively-yet not excluding-according to Dudai and colleagues' (47) theory of "trace dominance," the transient deficit may be due to a weak "memory trace" at 24 h posttraining that was amplified, rather than undergoing extinction, during the test the day after the conditioning . Nevertheless, Chabert et al (20) did report impaired long-term memory in the Morris water maze task, suggesting hippocampal-dependent memory dysfunction that corresponds with the current findings. The current results are discordant with previous reports (20), indicating this line of mice as displaying normal contextual fear conditioning, yet methodological differences in the conditioning paradigm, apparatus, and freezing quantification method between the present study and the previous report may account for this discrepancy.…”

“…Nevertheless, Chabert et al (20) did report impaired long-term memory in the Morris water maze task, suggesting hippocampal-dependent memory dysfunction that corresponds with the current findings. The current results are discordant with previous reports (20), indicating this line of mice as displaying normal contextual fear conditioning, yet methodological differences in the conditioning paradigm, apparatus, and freezing quantification method between the present study and the previous report may account for this discrepancy. Furthermore, these methodological considerations may also account for the discrepancies in cued fear conditioning; Ts65Dn exhibited deficits in cued fear conditioning (31), but GIRK2 triploid mice freezing in response to the cue did not differ from those of GIRK2 diploid mice, suggesting intact amygdala-dependent learning and memory.…”

“…A mouse line with trisomy for Kcnj6 alone (285E6/67) was established (19) that displays long-term spatial-memory deficits (20) with intact long-term potentiation (LTP) in hippocampal slices (21). The present study sought to investigate the effects of Kcnj6 trisomy in mice using behavioral and cellular physiology assays.…”

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

“…The telomeric part of Ts1cje is also telomeric on Ts65Dn and contains a region corresponding to the 21q22.1 and 21q22.3 cytological bands of HSA21 that is overlapped by the D21S17-ETS2 human region. One of the segmental trisomic mice with human fragments covering the D21S17-ETS2 region shows cognitive defect (Chabert et al 2004 ;Smith et al 1997 ). When the same fragments were incorporated in euploid mice ( Fig.…”

Editing of the serotonin 2C receptor pre-mRNA: Effects of the Morris Water Maze

“…For Down syndromerelated studies, it has the added attraction of being the most commonly used test, providing a robust phenotype in many mouse models (Escorihuela et al 1998;Sago et al 1998;Chabert et al 2004;Martinez-Cue et al 2005;Ahn et al 2006). There are, however, significant drawbacks to using the MWM when assaying a molecular phenotype.…”