Cognitive flexibility deficits differ between the sexes in a transchromosomic mouse model of Down syndrome

Individuals with Down syndrome (DS) exhibit cognitive and behavioral phenotypes, including intellectual disability, and reduced cognitive flexibility. The TcMAC21 DS mouse model (Tc(HSA21,CAG-EGFP)1Yakaz/J) has a freely segregating human chromosome 21 containing ∼93% of protein-coding genes and was hypothesized to show significant deficits in behavioral, learning, and memory tests. Examination of male and female TcMAC21 and control mice from postnatal day (P) 45-P62 showed TcMAC21 mice had lower body weight, with greater differences in males. Locomotor activity testing on P45 revealed TcMAC21 mice had greater activity than controls early in the session and increased time in the arena center later in the session, and a longer stride length in gait analysis. In the Morris water maze, TcMAC21 mice did not differ significantly from euploid littermates on acquisition of either cued or place training, though male (but not female) TcMAC21 mice showed significant deficits during reversal, providing the first demonstration of sex-specific impairment of cognitive flexibility in DS mouse models. These findings support the hypothesis that in young adults with DS, males may exhibit more severe deficits in cognitive flexibility than females.