Figure 3.

Endothelial cell APOE3 knockdown disrupts behavior. A through D, Spatial learning and memory assessed in the Morris water maze test. In the acquisition phase (A), there was an effect of trial ([F_(4,37)=21.7; P<0.001] P<0.05 for day 1 vs 2, 3, 4 and 5 when assessed by Bonferroni post hoc comparisons; Source Data File 1 in the Supplemental Material) but not Cre genotype. In the probe trial phase that tests memory (B and C), the number of entries (F_(1,40)=6.16; P=0.017) and time spent (F_(1,40)=4.31; P=0.044) in the previous platform area were lower in APOE3^Cre+/− mice compared with APOE3^Cre−/− mice. n=20 per Cre group. Data are expressed as a box plot depicting the minimum score, the lower quartile (25%), the median (50%, horizontal line), the upper quartile (75%), maximum values, and mean (+) and analyzed using general linear models. *P<0.05 for APOE3^Cre+/− vs APOE3^Cre−/− mice. D, Representative track plot of the probe trial phase. E through G, Acquisition and extinction of fear conditioned freezing measured in trace fear conditioning. E, In the acquisition phase, there was an effect of Cre genotype (F_(1,34)=7.15; P=0.011) with overall responses lower in APOE3^Cre+/− mice. In the extinction phases, there was no effect of Cre genotype on day 2 (F_(1,34)=0.19; P=0.66; F); however, on day 3 (G), there was a Cre genotype×trial interaction (F_(4,31)=3.76; P=0.013). Post hoc analysis revealed that these differences were driven by a lack of extinction in APOE3^Cre+/− mice and, therefore, higher freezing responses compared with APOE3^Cre−/− mice in later trials. There was also an effect of sex on the fear conditioned response (Figure S8) but no Cre×sex interaction. n≈20 per Cre genotype. A, E through G, Data expressed as mean±SEM analyzed using general linear models with repeated measures. *P<0.05 for APOE3^Cre+/− vs APOE3^Cre−/− mice when assessed by Bonferroni post hoc comparisons.