Inhibition of caspase-9 with Pen1-XBIR3 rescues the memory deficits of FDD
mice. Twenty-five days after a cannula was implanted in the lateral ventricle, mice were injected in the lateral ventricle either with 2 μl of PBS/23 μM Pen1-XBIR3, 2 μl of PBS/16 μM Pen1-CrmA, or 2 μl of PBS alone (WT/PBS N = 7, WT/Pen1-XBIR3 N = 8, WT/Pen1-CrmA N = 7, FDDKI/PBS N = 8, FDDKI/Pen1-XBIR3 N = 8, FDDKI/Pen1-CrmA N = 8). Injections were performed 1 h prior to the training section and 1 h before testing. WT and FDDKI mice spent the same amount of time exploring the two identical objects on day 1 (A). WT mice spent more time exploring the novel object 24 h later, while FDDKI mice do not recognize the new object (WT/Vehicle vs. FDDKI/Vehicle P = 0.0007) . Pen1-XBIR3 rescues this memory deficit (FDDKI/Pen1-XBIR3 vs. WT/Vehicle P = 0.79; FDDKI/Pen1-XBIR3 vs. WT/Pen1-XBIR3 P = 0.89; FDDKI/Pen1-XBIR3 vs. WT/Pen1-CrmA P = 0.37; FDDKI/Pen1-XBIR3 vs. FDDKI /Vehicle P = 0.0013; FDDKI/Pen1-XBIR3 vs. FDDKI/Pen1-CrmA P = 0.0027), while Pen1-CrmA does not (FDDKI/Pen1-CrmA vs. WT/Vehicle P = 0.0079; FDDKI/Pen 1-CrmA vs. WT/Pen1-XBIR3 P = 0.0038; FDDKI/Pen1-CrmA vs. WT/Pen1-CrmA P = 0.034; FDDKI/Pen1-CrmA vs. FDDKI /Vehicle P = 0.24). (B). C and D, The NOR test was repeated 5 days later without further treatments. The therapeutic effect of Pen1-XBIR3 is still significant (WT/Vehicle vs. FDDKI/Vehicle P = 0.0003; FDDKI/Pen1-XBIR3 vs. WT/Vehicle P = 0.046; FDDKI/Pen1-XBIR3 vs. WT/Pen1-XBIR3 P = 0.44; FDDKI/Pen1-XBIR3 vs. WT/Pen1-CrmA P = 0.95; FDDKI/Pen1-XBIR3 vs. FDDKI /Vehicle P = 0.03; FDDKI/Pen1-XBIR3 vs. FDDKI/Pen1-CrmA P = 0.028; FDDKI/Pen1-CrmA vs. WT/Vehicle P = 0.0002; FDDKI/Pen1-CrmA vs. WT/Pen1-XBIR3 P = 0.0025; FDDKI/Pen1-CrmA vs. WT/Pen1-CrmA P = 0.0038; FDDKI/Pen1-crmA vs. FDDKI/Vehicle P = 0.85). A paired two-sample t-test was used to test for significance between the discriminatory ratios between the groups.