Figure 9.
Figure 9. Deletion of metabotropic signaling downstream of astrocyte P2Y1R activation improves spatial memory and network hyperactivity. (A) Appps1+/− × Ip3r2−/− mice showed faster latencies to reach the hidden platform compared with Appps1+/− × Ip3r2+/+ mice (#, P < 0.05, two-way repeated-measures ANOVA and Bonferroni post hoc test). Moreover, they showed a similar learning curve as Appps1−/− × Ip3r2−/− mice, indicated by significantly shorter latencies on the last acquisition day compared with the first acquisition day, whereas no significant differences between these days were seen in Appps1+/− × Ip3r2+/+ mice (*, P < 0.05, two-way repeated-measures ANOVA and Bonferroni post hoc test; Appps1+/− × Ip3r2−/−, n = 19 mice; Appps1+/− × Ip3r2+/+, n = 10 mice; Appps1−/− × Ip3r2−/−, n = 21 mice; age of all groups, 8–9 mo). Data points represent the mean performance of mice during four trials/d. (B) The area under the curve (AUC) for the latency to reach the hidden platform was similar in Appps1+/− × Ip3r2−/− and Appps1−/− × Ip3r2−/−, but higher in Appps1+/− × Ip3r2+/+, mice (*, P < 0.05, one-way ANOVA followed by Holm–Sidak’s multiple comparisons test). (C) In the probe trial, the percentage of time mice spent in the target quadrant (TQ) was different from chance in Appps1+/− × Ip3r2−/− and Appps1−/− × Ip3r2−/− mice (P < 0.05, one-tailed one-sample t test), but not in Appps1+/− × Ip3r2+/+ mice. Moreover, Appps1+/− × Ip3r2+/+ spent significantly less time in the TQ compared with Appps1+/− × Ip3r2−/− and Appps1−/− × Ip3r2−/− mice (*, P < 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). (D) Swimming velocity of mice in across all days was similar in all groups (P > 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). (E) Activity of cortical astrocytes, measured using in vivo two-photon (2P) microscopy, in Appps1+/− × Ip3r2−/− mice was similar to Appps1−/− × Ip3r2−/− mice and significantly lower than in Appps1+/− × Ip3r2+/+ mice. Application of the P2Y1R agonist MRS2365 did not change astroglial activity in Appps1+/− × Ip3r2−/− mice, indicating effective suppression of signaling downstream of astrocytic P2Y1R activation (*, P < 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). All data are represented as mean ± SEM.

Deletion of metabotropic signaling downstream of astrocyte P2Y1R activation improves spatial memory and network hyperactivity. (A) Appps1+/− × Ip3r2−/− mice showed faster latencies to reach the hidden platform compared with Appps1+/− × Ip3r2+/+ mice (#, P < 0.05, two-way repeated-measures ANOVA and Bonferroni post hoc test). Moreover, they showed a similar learning curve as Appps1−/− × Ip3r2−/− mice, indicated by significantly shorter latencies on the last acquisition day compared with the first acquisition day, whereas no significant differences between these days were seen in Appps1+/− × Ip3r2+/+ mice (*, P < 0.05, two-way repeated-measures ANOVA and Bonferroni post hoc test; Appps1+/− × Ip3r2−/−, n = 19 mice; Appps1+/− × Ip3r2+/+, n = 10 mice; Appps1−/− × Ip3r2−/−, n = 21 mice; age of all groups, 8–9 mo). Data points represent the mean performance of mice during four trials/d. (B) The area under the curve (AUC) for the latency to reach the hidden platform was similar in Appps1+/− × Ip3r2−/− and Appps1−/− × Ip3r2−/−, but higher in Appps1+/− × Ip3r2+/+, mice (*, P < 0.05, one-way ANOVA followed by Holm–Sidak’s multiple comparisons test). (C) In the probe trial, the percentage of time mice spent in the target quadrant (TQ) was different from chance in Appps1+/− × Ip3r2−/− and Appps1−/− × Ip3r2−/− mice (P < 0.05, one-tailed one-sample t test), but not in Appps1+/− × Ip3r2+/+ mice. Moreover, Appps1+/− × Ip3r2+/+ spent significantly less time in the TQ compared with Appps1+/− × Ip3r2−/− and Appps1−/− × Ip3r2−/− mice (*, P < 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). (D) Swimming velocity of mice in across all days was similar in all groups (P > 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). (E) Activity of cortical astrocytes, measured using in vivo two-photon (2P) microscopy, in Appps1+/− × Ip3r2−/− mice was similar to Appps1−/− × Ip3r2−/− mice and significantly lower than in Appps1+/− × Ip3r2+/+ mice. Application of the P2Y1R agonist MRS2365 did not change astroglial activity in Appps1+/− × Ip3r2−/− mice, indicating effective suppression of signaling downstream of astrocytic P2Y1R activation (*, P < 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test). All data are represented as mean ± SEM.

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