Trisomy of Human Chromosome 21 Orthologs Mapping to Mouse Chromosome 10 Cause Age and Sex-Specific Learning Differences: Relevance to Down Syndrome

Abstract

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is the most common genetic cause of intellectual disability. The Dp10(1)Yey (Dp10) is a mouse model of DS that is trisomic for orthologs of 25% of the Hsa21 protein-coding genes, the entirety of the Hsa21 syntenic region on mouse chromosome 10. Trisomic genes include several involved in brain development and function, two that modify and regulate the activities of sex hormones, and two that produce sex-specific phenotypes as null mutants. These last four are the only Hsa21 genes with known sexually dimorphic properties. Relatively little is known about the potential contributions to the DS phenotype of segmental trisomy of Mmu10 orthologs. Here, we have tested separate cohorts of female and male Dp10 mice, at 3 and 9 months of age, in an open field elevated zero maze, rotarod, and balance beam, plus the learning and memory tasks, spontaneous alternation, puzzle box, double-H maze, context fear conditioning, and acoustic startle/prepulse inhibition, that depend upon the function of the prefrontal cortex, striatum, hippocampus, and cerebellum. We show that there are age and sex-specific differences in strengths and weaknesses, suggesting that genes within the telomere proximal region of Hsa21 influence the DS phenotype.

Keywords: Dp10(1)Yey; aging; double-H maze; female; hippocampus; intellectual disability; prefrontal cortex; prepulse inhibition; puzzle box; striatum.

Figure 1

Timeline. Order and time frame of tasks. Numbers indicate the week each task was carried out. Weeks with no task, mice were allowed to rest to reduce stress. EZM, elevated zero maze. CFC, context fear conditioning.

Figure 2

Performance in basic behaviors. Black bars, control; white bars, Dp10. Open field: (a) Total distance traveled, (b) Females and males, time at borders, and time in center. Elevated zero maze: (c) Females, open and closed areas; (d) Males, open and closed areas. Balance beam: (e) Time to reach goal box on narrowest beam; (f) % animals that completed the narrowest beam crossing. Spontaneous alternating Y-maze: (g) Females and males. Significant differences are indicated, p < 0.05, p < 0.01, p < 0.001 with *, **, and ***.

Figure 3

Rotarod performance. (a) Latency to fall. Black bars, controls; white bars, Dp10. Significant differences are indicated with *. (b) Regression, mouse weights vs. latency to fall. (c) Spearman correlation, r-values, and p-values; significant correlations are shown in bold.

Figure 4

Puzzle box. (a–d), 3-month, control, filled circles; Dp10, open circles; 9-month control, filled squares; Dp10, open squares. (c) 3 month, Dp10 female, filled circles; Dp10 male, open circles. Dashed boxes in (a,b) indicated areas enlarged in (c,d). (e) 3-month Dp10, females, filled circle; 3-month Dp10, males, open circle. *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001.

Figure 5

Double-H maze. Latency to reach the platform on successive days. (a) Females, 3-month-old; (b) Males, 3-month-old; (c) Females, 9-month-old; (d) Males 9-month-old. Filled circles and boxes, controls; open circles and boxes, Dp10; *, significant difference; ns, not significant.

Figure 6

Context fear conditioning. Percent time freezing in training (black bars) and test sessions (white bars). SC, shock-context; CS context-shock. C, control; Tr, Dp10; ns, not significant. (a) 3-month-old females; (b) 3-month-old males; (c) 9-month-old females; (d) 9-month-old males. *, p = 0.015, **, p = 0.002–0.008; ***, p = 0.0002; ****, p < 0.0001+.

Figure 7

Startle response and prepulse inhibition. (a) Startle amplitude. Black bars, control; white bars, Dp10. (b–e) 30 or 100 ms at 74, 78, or 82 dB. (b) Control females, black bars, 3-month-old; white bars, 9-month-old. (c) Dp10 males, black bars, 3-month-old; white bars, 9-month-old. (d) 9-month-old controls, black bars, male; white bars, female. (e) 9-month-old males, black bars, controls; white bars, Dp10. *, p ≤ 0.05; **, p ≤ 0.01.

Figure 8

Summary of sex, genotype, and age differences for all tasks. Solid lines indicate comparisons with significant differences between groups. Dashed lines indicate tasks showing no differences between any groups. PPI, prepulse inhibition of acoustic startle. CFC, context fear conditioning.