Context Fear Conditioning in Down Syndrome Mouse Models: Effects of Trisomic Gene Content, Age, Sex and Genetic Background

Down syndrome (DS), trisomy of the long arm of human chromosome 21 (Hsa21), is the most common genetic cause of intellectual disability (ID). Currently, there are no effective pharmacotherapies. The success of clinical trials to improve cognition depends in part on the design of preclinical evaluations in mouse models. To broaden understanding of the common limitations of experiments in learning and memory, we report performance in context fear conditioning (CFC) in three mouse models of DS, the Dp(16)1Yey, Dp(17)1Yey and Dp(10)1Yey (abbreviated Dp16, Dp17 and Dp10), separately trisomic for the human Hsa21 orthologs mapping to mouse chromosomes 16, 17 and 10, respectively. We examined female and male mice of the three lines on the standard C57BL/6J background at 3 months of age and Dp17 and Dp10 at 18 months of age. We also examined female and male mice of Dp17 and Dp10 at 3 months of age as F1 hybrids obtained from a cross with the DBA/2J background. Results indicate that genotype, sex, age and genetic background affect CFC performance. These data support the need to use both female and male mice, trisomy of sets of all Hsa21 orthologs, and additional ages and genetic backgrounds to improve the reliability of preclinical evaluations of drugs for ID in DS.