Down syndrome (DS), also known as trisomy 21, is the most common genetic cause of intellectual disability (ID). Although ID can be mild, the average intelligence quotient is in the range of 40–50. All individuals with DS will also develop the neuropathology of Alzheimer’s disease (AD) by the age of 30–40 years, and approximately half will display an AD-like dementia by the age of 60 years. DS is caused by an extra copy of the long arm of human chromosome 21 (Hsa21) and the consequent elevated levels of expression, due to dosage, of trisomic genes. Despite a worldwide incidence of one in 700–1,000 live births, there are currently no pharmacological treatments available for ID or AD in DS. However, over the last several years, very promising results have been obtained with a mouse model of DS, the Ts65Dn. A diverse array of drugs has been shown to rescue, or partially rescue, DS-relevant deficits in learning and memory and abnormalities in cellular and electrophysiological features seen in the Ts65Dn. These results suggest that some level of amelioration or prevention of cognitive deficits in people with DS may be possible. Here, we review information from the preclinical evaluations in the Ts65Dn, how drugs were selected, how efficacy was judged, and how outcomes differ, or not, among studies. We also summarize the current state of human clinical trials for ID and AD in DS. Lastly, we describe the genetic limitations of the Ts65Dn as a model of DS, and in the preclinical testing of pharmacotherapeutics, and suggest additional targets to be considered for potential pharmacotherapies.

Down syndrome (DS), caused by trisomy of human chromosome 21 (chr21), is the most common genetic cause of intellectual disability. The Ts65Dn mouse model of DS is trisomic for orthologs of 94 chr21‐encoded, confirmed protein‐coding genes and displays a number of behavioral deficits. Recently, Ts65Dn mice were shown to be hypersensitive to the locomotor stimulatory effects of the high‐affinity N‐methyl‐d‐aspartate (NMDA) receptor (NMDAR) channel blocker, MK‐801. This is consistent with the functions of several chr21 proteins that are predicted directly or indirectly to impact NMDAR function or NMDAR‐mediated signaling. In this study, we show that a second mouse model of DS, the Ts1Cje, which is trisomic for 70 protein‐coding genes, is also hypersensitive to MK‐801. To investigate the molecular basis for the responses to MK‐801, we have measured levels of a subset of chr21 and phosphorylated non‐chr21 proteins, in the cortex and hippocampus of Ts65Dn and Ts1Cje mice and euploid controls, with and without treatment with MK‐801. We show that in euploid mice, the chr21‐encoded proteins, TIAM1 and DYRK1A, and phosphorylation of AKT, ERK1/2 and the transcription factor ELK are involved in the MK‐801 response. However, in both Ts65Dn and Ts1Cje mice, levels of phosphorylation are constitutively elevated in naïve, unstimulated mice, and the MK‐801‐induced changes in TIAM1 and DYRK1A and in phosphorylation are either absent or abnormal, with both genotype and brain‐region‐specific patterns. These results emphasize the complexities of the pathway perturbations that arise with segmental trisomy.