FAD mice exhibited deficits in novel object recognition memory, working memory and spatial memory, which was rescued by EHMT1/2 inhibitors. (A) Bar graphs (mean ± SEM) showing the discrimination ratio of novel object recognition (NOR) tests in wild-type (WT) versus FAD mice (5–6 months old) without or with the treatment of BIX01294 (1 mg/kg, s.c. 3×) or UNC0642 (1 mg/kg, i.p. 3×). **P < 0.01, one-way ANOVA. (B) Representative heat maps illustrating the time spent in different locations of the arena for novel object recognition tests of all groups (blue: 0 s; red: ∼10 s). Locations of novel (denoted by an arrow) and familiar objects are labelled with the circles or squares. (C) Scatter plots showing the discrimination ratio of novel object recognition tests in each of the examined wild-type or FAD mice before and after the treatment with BIX01294 or UNC0642. *P < 0.05, ***P < 0.001, paired t-test. (D) Bar graphs (mean ± SEM) showing the percentage correctness in T-maze working memory (WM) tests in wild-type or FAD mice with or without BIX01294 treatment. *P < 0.05, **P < 0.01, two-way ANOVA. (E) Scatter plots showing the percentage correctness in T-maze tests in each of the examined FAD mice before and after BIX01294 treatment. ***P < 0.001, paired t-test. (F) Representative heat maps illustrating the time spent in different locations of the arena for Barnes maze tests during the memory phase (escape box removed) in wild-type versus FAD mice without or with the treatment of BIX01294 (1 mg/kg, s.c. 3×) or UNC0642 (1 mg/kg, i.p. 3×) (blue: 0 s; red: ∼10 s). Locations of the correct (indicated by an arrow) and seven incorrect holes are labelled with circles. (G) Bar graphs (mean ± SEM) showing the time spent on exploring the correct hole (T1) versus the seven incorrect holes (T2) in the memory phase of Barnes maze tests of all groups. *P < 0.05, **P < 0.01, ***P < 0.001, two-way ANOVA. (H) Bar graphs (mean ± SEM) showing the spatial memory index (T1/T2) of Barnes maze tests in wild-type versus FAD mice without or with the treatment of BIX01294 or UNC0642. ***P < 0.001, two-way ANOVA. (I) Scatter plots showing the spatial memory index in Barnes maze tests in each of the examined FAD mice before and after the treatment with BIX01294 or UNC0642. **P < 0.01, ***P < 0.001, paired t-test. (J) Plots (mean ± SEM) of spatial memory index in FAD mice treated with BIX01294 (1 mg/kg, s.c. 3×) or saline at different time points. **P < 0.01, ***P < 0.001, saline versus BIX01294; ##P < 0.01, ###P < 0.001, pre- versus post-injection, two-way ANOVA. Each set of the experiments was replicated between four and five times.