Inheritance of the ε4 allele for apolipoprotein E (apoE) increases the risk of Alzheimer disease and memory impairment, whereas ε2 decreases these risks compared with the most common ε3 allele, but the mechanism for these effects is unknown. Long-term potentiation (LTP) is an experimentally induced increase in synaptic efficacy that models memory. Using hippocampal slices from wild type (WT), apoE knockout (apoE-KO), and targeted replacement mice expressing human apoE2, E3, or E4 (apoE-TR) we found that although all strains had comparable basal synaptic transmission, LTP was significantly greater in WT and apoE3-TR than in apoE-KO, apoE2-TR or apoE4-TR. This novel system may be used to investigate the mechanisms of apoE isoform dependent modulation of susceptibility to memory impairment.