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Genetics. 2014 Jul;197(3):899-912. doi: 10.1534/genetics.114.165241. Epub 2014 Apr 21.

Cognition and hippocampal plasticity in the mouse is altered by monosomy of a genomic region implicated in Down syndrome.

Author information

1
Systems Biology Programme, Centre for Genomic Regulation, Universitat Pompeu Fabra, and Centro de Investigación Biomédica en Red de Enfermedades Raras, E-08003 Barcelona, Spain.
2
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, 67404 Illkirch, France Centre National de la Recherche Scientifique, UMR7104, Illkirch, France Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France Université de Strasbourg, 67400 Illkirch, France.
3
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, 67404 Illkirch, France.
4
División de Neurociencias, Universidad Pablo de Olavide, 41013 Sevilla, Spain.
5
Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.
6
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, 67404 Illkirch, France Centre National de la Recherche Scientifique, UMR7104, Illkirch, France Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France Université de Strasbourg, 67400 Illkirch, France Institut Clinique de la Souris, PHENOMIN, Groupement d'Intérêt Economique Centre Européen de Recherche en Biologie Moléculaire, 67404 Illkirch, France herault@igbmc.fr.

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.

KEYWORDS:

aneuploidy; genetic dosage; intellectual disabilities; mouse model; trisomy 21

PMID:
24752061
PMCID:
PMC4096369
DOI:
10.1534/genetics.114.165241
[Indexed for MEDLINE]
Free PMC Article

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