Figure 8.
Figure 8. Chronic P2Y1R inhibition reverses spatial reference learning and memory deficits in APPPS1 mice. (A) Mice were treated with P2Y1R-selective drugs or vehicle through osmotic minipumps for 5 wk and tested in the Barnes maze test during continuous pump infusion. (B) The learning curve of the latency to the escape box was similar in all groups except for MRS2365-treated APPPS1 mice, which showed longer latencies compared with WT mice on days 2 and 4 (#, P < 0.05, two-way repeated-measures ANOVA and Bonferroni post hoc test). Data points represent the mean performance of mice during four trials/d (APPPS1 + MRS2179, n = 8 mice; APPPS1 + vehicle, n = 8 mice; APPPS1 + BPTU, 11 mice; APPPS1 + MRS2365, 7 mice; WT + MRS2179, n = 8 mice; WT + vehicle, n = 7 mice; age of all groups, 10–12 mo). (C) The area under the curve (AUC) for the latency to the escape box was higher in MRS2365-treated APPPS1 mice and similar in all other groups (*, P < 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). Veh, vehicle-treated. (D and E) The learning curve of the moved distance was similar in all groups except for MRS2365-treated APPPS1 mice, which moved longer distances to reach the escape box compared with WT mice on days 2 and 3 (#, P < 0.05, two-way repeated-measures ANOVA and Bonferroni post hoc test). Similarly, the AUC for the distance moved to the escape box was higher in MRS2365-treated APPPS1 mice and similar in all other groups (*, P < 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). (F) The number of “hole errors” as a measure of nonspatial over spatial search strategies was higher on day 4 in vehicle-treated APPPS1 and MRS2365-treated mice compared with MRS2179-treated or BPTU-treated APPPS1 mice as well as MRS2179-treated or vehicle-treated WT mice (#, P < 0.05, two-way repeated-measures ANOVA and Bonferroni post hoc test). Moreover, MRS2179-treated and BPTU-treated APPPS1 mice as well as both WT groups made significantly fewer errors on day 4 versus day 1 (P < 0.001), whereas vehicle-treated APPPS1 mice did not (*, P < 0.05, two-way repeated-measures ANOVA and Bonferroni post hoc test). (G) Cumulative hole errors across all days were higher in vehicle-treated APPPS1 mice compared with all other groups, but similar to MRS2365-treated APPPS1 mice (*, P < 0.05, one-way ANOVA and Dunnett’s multiple comparison test). (H) Targeted (spatial) versus serial (nonspatial) search strategies in MRS2179-treated and vehicle-treated transgenic mice. (I) Probe trial data. The percentage of time mice spent in the target quadrant (TQ) was different from chance (P < 0.05, one-tailed one-sample t test) except in vehicle-treated and MRS2365-treated APPPS1 mice. Vehicle-treated and MRS2365-treated APPPS1 mice did not show a preference for the TQ compared with all other quadrants (AO; *, P < 0.05, Wilcoxon matched-pairs signed rank test), and time spent in the TQ was significantly less for vehicle-treated APPPS1 mice compared with WT mice (#, P < 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). (J) Velocity of mice in the Barnes maze across all days was similar in all groups (P > 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). All data are represented as mean ± SEM.

Chronic P2Y1R inhibition reverses spatial reference learning and memory deficits in APPPS1 mice. (A) Mice were treated with P2Y1R-selective drugs or vehicle through osmotic minipumps for 5 wk and tested in the Barnes maze test during continuous pump infusion. (B) The learning curve of the latency to the escape box was similar in all groups except for MRS2365-treated APPPS1 mice, which showed longer latencies compared with WT mice on days 2 and 4 (#, P < 0.05, two-way repeated-measures ANOVA and Bonferroni post hoc test). Data points represent the mean performance of mice during four trials/d (APPPS1 + MRS2179, n = 8 mice; APPPS1 + vehicle, n = 8 mice; APPPS1 + BPTU, 11 mice; APPPS1 + MRS2365, 7 mice; WT + MRS2179, n = 8 mice; WT + vehicle, n = 7 mice; age of all groups, 10–12 mo). (C) The area under the curve (AUC) for the latency to the escape box was higher in MRS2365-treated APPPS1 mice and similar in all other groups (*, P < 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). Veh, vehicle-treated. (D and E) The learning curve of the moved distance was similar in all groups except for MRS2365-treated APPPS1 mice, which moved longer distances to reach the escape box compared with WT mice on days 2 and 3 (#, P < 0.05, two-way repeated-measures ANOVA and Bonferroni post hoc test). Similarly, the AUC for the distance moved to the escape box was higher in MRS2365-treated APPPS1 mice and similar in all other groups (*, P < 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). (F) The number of “hole errors” as a measure of nonspatial over spatial search strategies was higher on day 4 in vehicle-treated APPPS1 and MRS2365-treated mice compared with MRS2179-treated or BPTU-treated APPPS1 mice as well as MRS2179-treated or vehicle-treated WT mice (#, P < 0.05, two-way repeated-measures ANOVA and Bonferroni post hoc test). Moreover, MRS2179-treated and BPTU-treated APPPS1 mice as well as both WT groups made significantly fewer errors on day 4 versus day 1 (P < 0.001), whereas vehicle-treated APPPS1 mice did not (*, P < 0.05, two-way repeated-measures ANOVA and Bonferroni post hoc test). (G) Cumulative hole errors across all days were higher in vehicle-treated APPPS1 mice compared with all other groups, but similar to MRS2365-treated APPPS1 mice (*, P < 0.05, one-way ANOVA and Dunnett’s multiple comparison test). (H) Targeted (spatial) versus serial (nonspatial) search strategies in MRS2179-treated and vehicle-treated transgenic mice. (I) Probe trial data. The percentage of time mice spent in the target quadrant (TQ) was different from chance (P < 0.05, one-tailed one-sample t test) except in vehicle-treated and MRS2365-treated APPPS1 mice. Vehicle-treated and MRS2365-treated APPPS1 mice did not show a preference for the TQ compared with all other quadrants (AO; *, P < 0.05, Wilcoxon matched-pairs signed rank test), and time spent in the TQ was significantly less for vehicle-treated APPPS1 mice compared with WT mice (#, P < 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). (J) Velocity of mice in the Barnes maze across all days was similar in all groups (P > 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). All data are represented as mean ± SEM.

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