Down syndrome (DS) is a multi-faceted condition resulting in the most common genetic form of intellectual disability. Mouse models of DS, especially the Ts65Dn model, have been pivotal in furthering our understanding of the genetic, molecular and neurobiological mechanisms that underlie learning and memory impairments in DS. Cognitive and pharmacological insights from the Ts65Dn mouse model have led to remarkable translational progress in the development of therapeutic targets and in the emergence of DS clinical trials. Unravelling the pathogenic role of trisomic genes on human chromosome 21 and the genotype-phenotype relationship still remains a pertinent goal for tackling cognitive deficits in DS.

Down syndrome (DS) is one of many causes of intellectual disability (ID), others including but not limited to, fetal alcohol syndrome, Fragile X syndrome, Rett syndrome, Williams syndrome, hypoxia, and infection. Down syndrome is characterized by a number of neurobiological problems resulting in learning and memory deficits and early onset Alzheimer's disease. The cognitive impairment in people with DS is virtually universal but varies considerably with respect to expressivity and severity. Significant advances in medical treatment and social inclusion have increased longevity in people with DS resulting in an increased aging population, thus highlighting the significance of early onset of dementia and the importance of identifying pharmacotherapies to treat DS-associated health complications in adults. Given its prevalence and established mouse models, this review will focus on ID in the DS population; specifically, the superimposed effect of aging on the complications already manifest in DS adults and the cognitive insights gained from studies on mouse models of DS.

Abnormalities of chromosome copy number are called aneuploidies and make up a large health load on the human population. Many aneuploidies are lethal because the resulting abnormal gene dosage is highly deleterious. Nevertheless, some whole chromosome aneuploidies can lead to live births. Alterations in the copy number of sections of chromosomes, which are also known as segmental aneuploidies, are also associated with deleterious effects. Here we examine how aneuploidy of whole chromosomes and segmental aneuploidy of chromosomal regions are modeled in the mouse. These models provide a whole animal system in which we aim to investigate the complex phenotype-genotype interactions that arise from alteration in the copy number of genes. Although our understanding of this subject is still in its infancy, already research in mouse models is highlighting possible therapies that might help alleviate the cognitive effects associated with changes in gene number. Thus, creating and studying mouse models of aneuploidy and copy number variation is important for understanding what it is to be human, in both the normal and genomically altered states.

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Chromosome copy number aberrations, anueploidies, are common in the human population but generally lethal. However, trisomy of human chromosome 21 is compatible with life and people born with this form of aneuploidy manifest the features of Down syndrome, named after Langdon Down who was a 19th century British physician who first described a group of people with this disorder. Down syndrome includes learning and memory deficits in all cases, as well as many other features which vary in penetrance and expressivity in different people. While Down syndrome clearly has a genetic cause - the extra dose of genes on chromosome 21 - we do not know which genes are important for which aspects of the syndrome, which biochemical pathways are disrupted, or, generally how design therapies to ameliorate the effects of these disruptions. Recently, with new insights gained from studying mouse models of Down syndrome, specific genes and pathways are being shown to be involved in the pathogenesis of the disorder. This is opening the way for exciting new studies of potential therapeutics for aspects of Down syndrome, particularly the learning and memory deficits.