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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Cluster Analysis
  • Cognition*
  • Conditioning, Psychological
  • Disease Models, Animal
  • Down Syndrome / genetics*
  • Down Syndrome / physiopathology*
  • Exploratory Behavior
  • Gene Expression Regulation
  • Genome*
  • Hippocampus / pathology
  • Hippocampus / physiopathology*
  • Learning
  • Long-Term Potentiation
  • Mice, Inbred C57BL
  • Monosomy / genetics*
  • Monosomy / physiopathology
  • Motor Activity
  • Neuronal Plasticity*
  • Social Behavior