Working memory.

<p>A: Alternation rate in Y-maze; B: Number of arm entries in Y-maze; C: Alternation rate in T-maze; D: Averaged time spent on T-maze test. Mean ± SEM. Number of tested animals WT = 22; TTS = 12. **p < 0.01 and ***p<0.001, significantly different from WT mice.</p

Down Syndrome Cognitive Phenotypes Modeled in Mice Trisomic for All HSA 21 Homologues

<div><p>Down syndrome (DS), trisomy for chromosome 21, is the most common genetic cause of intellectual disability. The genomic regions on human chromosome 21 (HSA21) are syntenically conserved with regions on mouse chromosomes 10, 16, and 17 (Mmu10, Mmu16, and Mmu17). Recently, we created a genetic model of DS which carries engineered duplications of all three mouse syntenic regions homologous to HSA21. This ‘triple trisomic’ or TTS model thus represents the most complete and accurate murine model currently available for experimental studies of genotype-phenotype relationships in DS. Here we extended our initial studies of TTS mice. Locomotor activity, stereotypic and repetitive behavior, anxiety, working memory, long-term memory, and synaptic plasticity in the dentate gyrus were examined in the TTS and wild-type (WT) control mice. Changes in locomotor activity were most remarkable for a significant increase in ambulatory time and a reduction in average velocity of TTS mice. No changes were detected in repetitive and stereotypic behavior and in measures of anxiety. Working memory showed no changes when tested in Y-maze, but deficiency in a more challenging T-maze test was detected. Furthermore, long-term object recognition memory was significantly reduced in the TTS mice. These changes were accompanied by deficient long-term potentiation in the dentate gyrus, which was restored to the WT levels following blockade of GABAA receptors with picrotoxin (100 μM). TTS mice thus demonstrated a number of phenotypes characteristic of DS and may serve as a new standard by which to evaluate and direct findings in other less complete models of DS.</p></div

Major behavioral and physiological phenotypes in mouse genetic models of Down syndrome.

<p>‘☑’–Results of this study;</p><p>‘↔’—No change;</p><p>‘↑’–Increased;</p><p>‘↓’—Reduced;</p><p>‘─’–Data not published.</p><p>Major behavioral and physiological phenotypes in mouse genetic models of Down syndrome.</p

Spontaneous locomotor activity.

<p>A-C: Ambulatory distance; D-F: Ambulatory time; G-I: Resting time; J-K: Average velocity. The values averaged for 2-min sequential periods (A, D, G, J) and for the total 10-min testing period (B, E, H, K) are shown. Also, the percentage of distance and time on the arena periphery (C, F, I) are shown. L: Number of pellets dropped during the test. All results are mean ± SEM. Number of mice examined: WT = 22; TTS = 12. *p < 0.05, **p < 0.01, and ***p<0.001, significantly different from WT mice.</p

Mouse genetic models of DS and breeding schema of TTS mice.

<p><b>A:</b> Mouse genetic models. <i>Left</i>: Correspondence of syntenic genomic regions on human chromosome 21 (HSA21) to mouse chromosomes (Mmu) 10, 16, and 17. <i>Right</i>: Schema of the triplicated genomic regions in several notable mouse models of DS. Mouse and human genomic regions are shown in green and blue respectively. Triplicated genomic regions not present on HSA21 and, therefore, not triplicated in DS, are shown in black. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134861#pone.0134861.t001" target="_blank">Table 1</a> for details regarding the size and boundaries of the triplicated regions. <b>B:</b> Breeding schema of TTS mice. First, Dp(10)1Yey/+, Dp(16)1Yey/+, and Dp(17)1Yey/+ mice (green rectangles) were generated by triplications of the corresponding syntenic regions. Next, compound Dp(10)1Yey/+;Dp(16)1Yey/+ mice (black rectangle) were generated by crossing Dp(10)1Yey/+ and Dp(16)1Yey/+ mutant mice. Finally, TTS mice (red rectangle) were generated by crossing Dp(10)1Yey/+;Dp(16)1Yey/+ and Dp(17)1Yey/+ mice.</p

Novel object recognition.

<p>A: The time spent on investigation of the objects during the testing phase of the experiment; B: Discrimination index. Mean ± SEM; *p < 0.05, significantly different from WT mice.</p

Stereotypic and repetitive behaviors.

<p>A: Time spent on stereotypic movements; B: Jumping time; C: The number of jumps; D: Vertical counts; E: Vertical time; F: Percentage of buried glass marbles. Mean ± SEM. Number of tested animals WT = 22; TTS = 12. *p < 0.05 and **p < 0.01, significantly different from WT mice.</p

Synaptic efficiency and plasticity in the dentate gyrus.

<p>A: Input-output relationship in the DG. Evoked responses were similar in MML of WT and TTS DG (blue and red markers respectively). B: Time course of the averaged initial slope of field EPSPs during the experiment. Tetanization (arrow) evoked stable LTP in WT, but not in TTS mice (blue and red markers respectively). The results are mean ± SEM. The number of slices/mice examined: WT = 9/4; TTS = 8/4. C: Suppression of inhibition by picrotoxin allowed for induction of normal LTP in the TTS slices. The results are mean ± SEM. The number of slices/mice examined: WT = 6/3; TTS = 7/3.</p

Long-term memory: Novel object recognition with the retention period of 24 hours.

<p>A: Time of object exploration during acquisition. There was no difference between the groups, and no effect of JZL184-treatment on the exploration time. B: Testing phase. Left: Time of object exploration during testing was smaller in vehicle-treated Ts65Dn vs. 2N mice. There was no such difference between the JZL184-treated Ts65Dn and 2N groups. Right: Discrimination index was smaller in the vehicle-treated Ts65Dn vs. 2N mice. JZL184-treatment significantly increased the discrimination index in Ts65Dn mice, but had no effect on the performance of their 2N littermates.</p

Working memory: performance in Y-maze.

<p>A. The baseline rate of spontaneous alternations in Y-maze was lower in the vehicle-treated Ts65Dn vs. 2N mice, reflecting an impairment of working memory. JZL184-treatment had no effect on the performance of both 2N and Ts65Dn mice suggesting no effect on working memory. B. The number of ‘arm entries’ during the Y-maze test was greater in vehicle-treated Ts65Dn vs. 2N mice reflecting increased locomotion of Ts65Dn mice. JZL184-treatment reduced this parameter to the levels seen in 2N animals.</p