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. 2017 Jul 24;114(32):8631–8636. doi: 10.1073/pnas.1708106114

Fig. 2.

Fig. 2.

Rescue of neuronal hyperactivity and hypersynchrony. (A and B) (Top) Representative in vivo two-photon fluorescence images of OGB-1 acetoxymethyl ester-labeled layer 2/3 cell populations in the frontal cortex and corresponding activity maps obtained from untreated (A) and NB-360–treated (B) APP23xPS45 mice, illustrating the restoration of normal activity levels by BACE inhibitor treatment. In the activity maps, neurons are color-coded according to their activity status; yellow dashed circles delineate Aβ plaques. Note that plaques are labeled by OGB-1, and that astrocytes appear brighter than the surrounding neurons owing to their higher resting calcium levels. (Bottom) Activity traces from five example neurons marked in the top panel. (C–E) Summary histograms of activity in all recorded neurons from WT mice (C; n = 1,362 cells in 5 mice), untreated APP23xPS45 mice (D; n = 1,822 cells in 8 mice), and treated APP23xPS45 mice (E; n = 2,213 cells in 10 mice), highlighting the marked reduction of abnormal cortical hyperactivity after treatment. Dashed lines indicate the threshold used to identify hyperactive neurons (marked in red). (F) Fractions of hyperactive neurons in WT mice (blue bar; n = 5), untreated APP23xPS45 mice (red bar; n = 8), and treated APP23xPS45 mice (green bar; n = 10) [2.48 ± 1.20% for WT vs. 50.60 ± 9.53% for control vs. 11.15 ± 4.62% for NB-360; F(2,20) = 13.66, P = 0.0002; Tukey´s post hoc comparisons: P < 0.001 for WT vs. control, P < 0.001 for control vs. NB-360, P > 0.05 for WT vs. NB-360]. Gray circles represent individual animals. (G) FA-extracted Aβ levels correlate positively with the fractions of hyperactive neurons in APP23xPS45 mice (n = 22 mice). Untreated and treated (after short-term and long-term treatment) APP23xPS45 mice are color-coded; each circle represents an individual animal. (H) Fractions of hyperactive neurons correlate positively with the degree of synchrony between neurons in APP23xPS45 mice (n = 18 mice). ***P < 0.001. Tg = APP23xPS45 model. ns, not significant. Error bars represent mean ± SEM.