Attentional performance, impulsivity, and related neurotransmitter systems in apoE2, apoE3, and apoE4 female transgenic mice

Rationale: The apolipoprotein E (apoE) genotype influences cognitive performance in humans depending on age and sex. While the detrimental role of the apoE4 isoform on spatial learning and memory has been well-established in humans and rodents, less is known on its impact on the executive functions. Objectives: We aimed to evaluate the effect of apoE isoforms (apoE2, apoE3, apoE4) on visuospatial attention and inhibitory control performance in female transgenic mice, and to determine the neurochemical and neuropharmacological basis of this potential relationship. Methods: Female mice carrying apoE2, apoE3, and apoE4 were trained in the five-choice serial reaction time task (5-CSRTT). Upon a stable performance, we manipulated the inter-trial interval and the stimulus duration to elicit impulsive responding and engage attention respectively. We further performed a pharmacological challenge by administering cholinergic and GABAergic agents. Finally, we analyzed the levels of brain amino acids and monoamines by using reversed phase high-performance liquid chromatography (HPLC). Results: ApoE4 mice showed a deficient inhibitory control as revealed by increased perseveration and premature responding. When attention was challenged, apoE4 mice also showed a higher drop in accuracy. The adverse effect of scopolamine on the task was attenuated in apoE4 mice compared to apoE2 and apoE3. Furthermore, apoE4 mice showed less dopamine in the frontal cortex than apoE2 mice. Conclusions: We confirmed that the apoE genotype influences attention and inhibitory control in female transgenic mice. The influence of apoE isoforms in the brain neuromodulatory system may explain the cognitive and behavioral differences attributable to the genotype.