Down syndrome (DS) is the most common genetically-defined cause of intellectual disability. Neurodevelopmental deficits displayed by individuals with DS are generally global, however, disproportionate deficits in cognitive processes that depend heavily on the hippocampus and prefrontal cortex are also well documented. Additionally, DS is associated with relative strengths in visual processing and visuospatial short-term memory, and weaknesses in the verbal domain. Although reports of pharmacological rescuing of learning and memory deficits in mouse models of DS abound in the literature, proving the principle that cognitive ability of persons with DS can be boosted through pharmacological means is still an elusive goal. The design of customized batteries of neuropsychological efficacy outcome measures is essential for the successful implementation of clinical trials of potential cognitive enhancing strategies. Here, we review the neurocognitive phenotype of individuals with DS and major broad-based test batteries designed to quantify specific cognitive domains in these individuals, including the one used in a pilot trial of the drug memantine. The main goal is to illustrate the essential considerations in planning trials to enhance cognitive functions in individuals with DS, which should also have implications for the design of similar studies in individuals with other forms of intellectual disability.

Down syndrome (DS), which results from the complete or partial trisomy of chromosome 21 (trisomy-21), is the most common genetically defined cause of intellectual disability. Trisomy-21 also produces, or is associated with, many neurodevelopmental phenotypes and neurological comorbidities, including delays and deficits in fine and gross motor development. The Ts65Dn mouse is the most studied animal model for DS and displays the largest known subset of DS-like phenotypes. To date, however, only a small number of developmental phenotypes have been quantitatively defined in these animals. Here, we used a commercially available high-speed, video-based system to record and analyze the gait of Ts65Dn and euploid control mice. Longitudinal treadmill recordings were performed from p17 to p35. One of the main findings was the detection of genotype- and sex-dependent developmental delays in the emergence of consistent, progressive-intensity gait in Ts65Dn mice when compared to control mice. Gait dynamic analysis showed wider normalized front and hind stances in Ts65Dn mice compared to control mice, which may reflect deficits in dynamic postural balance. Ts65Dn mice also displayed statistically significant differences in the variability in several normalized gait measures, which were indicative of deficits in precise motor control in generating gait.