Cortical astrocytes are hyperactive in APPPS1 mice, and MRS2179 reduces cortical hyperactivity. (A) APPPS1 mice or WT littermates were treated with P2Y1R-selective drugs through osmotic minipumps for a total of 6 wk and imaged through cranial windows. (B) In vivo two-photon microscopy of calcium activity, measured with OGB-1, in astrocytes and neurons in the cortex of APPPS1 mice. Astrocytes were identified by SR101 colabeling (arrows). Aβ plaques were labeled with methoxy-X04 (arrowhead). Bar, 50 µm. (C and D) Astroglial hyperactivity was prominent in vehicle-treated (Veh) APPPS1 mice, but was reduced to levels similar to those of WT littermates in MRS2179-treated or BPTU-treated APPPS1 mice. In contrast, astroglial activity was significantly increased in MRS2365-treated mice (APPPS1 + MRS2179, n = 6 mice; APPPS1 + BPTU, n = 6 mice; APPPS1 + MRS2365, n = 6 mice; APPPS1 + vehicle, n = 6 mice; WT + MRS2179, n = 3 mice; WT + vehicle, n = 4 mice; age, 11 mo; *, P < 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test; mean ± SEM). (E and F) The frequency of spontaneous neuronal events was significantly reduced by MRS2179 and BPTU and nonsignificantly increased by MRS2365 in transgenic mice (*, P < 0.05, Kruskal–Wallis test followed by Dunn’s multiple comparisons test; same mice as in C; mean ± SEM). The cumulative distributions of spontaneous neuronal calcium transients in MRS2179-treated or BPTU-treated APPPS1 mice were not different from those of vehicle-treated or MRS2179-treated WT mice (P > 0.05, Kolmogorov–Smirnov test) but were significantly different from those of vehicle-treated or MRS2365-treated APPPS1 mice (P < 0.05, Kolmogorov–Smirnov test).