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

Individuals with Down syndrome (DS) exhibit cognitive and behavioral phenotypes, including intellectual disability and reduced cognitive flexibility. The TcMAC21 mouse model of DS [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 to P62 showed that TcMAC21 mice had lower body weight than controls, with greater differences in males than in females. Locomotor activity testing on P45 revealed that 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 in acquisition of either cued or place training, although male (but not female) TcMAC21 mice showed significant deficits during reversal, providing the first demonstration of sex-specific impairment of cognitive flexibility in a mouse model of DS. These findings support the hypothesis that, in young adults with DS, males exhibit more severe deficits in cognitive flexibility than females.