Mouse Models for Down Syndrome-Associated Developmental Cognitive Disabilities

Abstract

Down syndrome (DS) is mainly caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is a leading genetic cause for developmental cognitive disabilities in humans. The mouse is a premier model organism for DS because the regions on Hsa21 are syntenically conserved with three regions in the mouse genome, which are located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. With the advance of chromosomal manipulation technologies, new mouse mutants have been generated to mimic DS at both the genotypic and phenotypic levels. Further mouse-based molecular genetic studies in the future may lead to the unraveling of the mechanisms underlying DS-associated developmental cognitive disabilities, which would lay the groundwork for developing effective treatments for this phenotypic manifestation. In this review, we will discuss recent progress and future challenges in modeling DS-associated developmental cognitive disability in mice with an emphasis on hippocampus-related phenotypes.

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

“…Reference memory was measured by the ability to locate the platform in the MWM. Working memory was measured by the number of errors in a version of the 8-arm radial maze (RAM) (Liu et al 2011 ;Matynia et al 2002 ). Episodic memory was assessed using the novel object recognition test (Ennaceur and Delacour 1988 ;Lyon et al 2012 ).…”

Exaggerated NMDA mediated LTD in a mouse model of Down syndrome and pharmacological rescuing by memantine

“…These findings are consistent with the so-called "mGluR hypothesis of FXS," which posits that FMRP normally regulates protein synthesis downstream from Group I mGluRs (mGluR1 and mGluR5) and, in its absence, mGluR-dependent protein synthesis becomes abnormal . Interestingly, exaggerated LTD has also been found in the same area of the hippocampus of the Ts65Dn mouse (Siarey et al 1999), which is the most widely studied animal model for DS (for review, see Patterson and Costa 2005;Costa 2011;Liu et al 2011). However, to date, no attempt has been made to pharmacologically identify whether there is any neurotransmitter receptor specificity to this phenomenon, similar to what has been done for the FMR1 null mutant mouse.…”

Nest building is impaired in the Ts65Dn mouse model of Down syndrome and rescued by blocking 5HT2a receptors

“…These models range from single-gene over-expressing transgenes to partial segmental trisomic mice (TS) (Liu et al, 2011;Salehi, Faizi, Belichenko, & Mobley, 2007). Ts65Dn mice carry three copies of parts of murine chromosome 16 (Mmu16) and Mmu17 that are homologous to about half of the human chromosome 21 genes triplicated in DS or about 150 genes (Creau, 2012).…”