Figure 4. ISRIB reverses defective hippocampal LTP and memory in APPswe/PS1ΔE9 mice.
10–13 month-old APPswe/PS1ΔE9 mice (or WT littermates) were treated daily for 2 weeks with ISRIB (0.25 mg/kg, i.p.) prior to behavioral analysis. (A) Field excitatory post-synaptic potential recordings in acute hippocampal slices from WT or APPswe/PS1 E9 mice exposed to vehicle or 0.2 μM ISRIB (N = 13–26 slices from 6–9 mice/group). (B) On top - Representative slopes for fEPSP measurements. “1” is representative of the baseline, and “2” is representative of potentiation. Graph is representative of field excitatory post-synaptic potentials 90 min after tetanic stimulation. (C) Dendritic spine density was analyzed in apical dendrites of neurons from the CA1 region of the hippocampus. Each dot is representative of one segment using in the analysis (N = 4 mice/group) (D) Mice were trained for 5 days in the MWM, and latency time to reach the platform was recorded (N = 10–15 mice/group). Symbols represent means ± SE of the latency times to find the platform on each consecutive day of training. (E) On the 6th day, the platform was removed, and mice were allowed to freely explore the pool for 1 minute. Total time spent in the target quadrant during the probe trial was measured (N = 10–15 mice per group). (F) Contextual fear conditioning of WT or APPswe/PS1ΔE9 mice treated with ISRIB (N = 10–15 mice/group) or saline. (G) Representative photomontage illustrating presence of plaques (6E10 immunoreactivity; green channel) in the dorsal hippocampus of APPSwe/PS1ΔE9 mice treated with vehicle (left) or with ISRIB (right) (N = 4–5 mice/group; scale bar = 200 μm). (H, K) Optical zoom images of regions identified by dashed rectangles in panel G. (I) Average plaque area in the hippocampi of APPswe/PS1ΔE9 mice treated with vehicle or ISRIB (N = 4–5 mice/group). (J) Total number of plaques normalized by hippocampal area. (L, M) Total Aβ42 measured by ELISA in hippocampal (L) or cortical (M) homogenates of APPSwe/PS1ΔE9 mice treated with vehicle or ISRIB (N = 4 mice/group). *p < 0.05, ****p < 0.0001 Two-way ANOVA followed by Dunnet’s post-hoc test, except for panel 1A, evaluated by Repeated Measures Two-Way ANOVA, followed by Tukey’s post hoc analysis. Dots represent individual mice.