Figure 7: P2Y1 receptor inhibition normalizes astrocytic hyperactivity.

(a) P2Y1 receptors are predominantly expressed by reactive astrocytes (stained with GFAP antibody; arrows indicate co-expression) around Aβ plaques (stained with methoxy-XO4), indicating a strong spatial overlap of P2Y1 receptor expression and the area where astrocytic hyperactivity is highest. Scale bar, 20 μm. (b) Frequency histogram revealed that the fraction of hyperactive astrocytes was significantly reduced after P2Y1 inhibition in APPPS1 mice (P<0.05, χ²-test), while the fraction of active astrocytes remained unchanged. (c) The P2Y1 receptor blocker MRS2179 significantly reduced the frequency of astrocyte activity in all active astrocytes (n=123 astrocytes from n=4 mice; 0.67±0.11 versus 0.22±0.20 transients per min; P<0.05, Mann–Whitney test; 500 μM). Baseline activity was recorded during topical application of ACSF and again after drug application. (d) In contrast, MRS2179 had no influence on the frequency of spontaneous astrocyte activity in wild-type littermates (n=111 astrocytes from n=3 mice; P>0.05, Mann–Whitney test).