CRE mice exhibit hyperactive and impulsive behavior affecting their learning and retention performances

Abstract CRE recombinase is a protein that recognizes and mediates site-specific recombination between loxP site sequences. The Cre/loxP recombination system has become a useful tool for genetic manipulation. Spatial regulation of recombination can be achieved by using cell type-specific promoters that drive expression of CRE in the tissue of interest. The temporal regulation can be obtained with CreER recombinase, which consists of Cre fused to mutated hormone-binding domain of the estrogen receptor (ER). In the more improved versions of the construct, the CRE - mediated gene regulation can be controlled both spatially and temporally, by combining tissue-specific expression of a CreER recombinase with its tamoxifen-dependent activity. We recently generated and characterized an astrocyte specific mutant of the lipolysis-stimulated lipoprotein receptor lsr gene by crossing Glast ERT2 mice with floxed lsr mice (El Hajj et al., 2022). During the behavioral analysis of generated mice, we identified specific hyperactive traits in the Glast ERT2 mice (CRE mice) that prevented them from being used as a control group. Here we further assessed the hyperactive trait of those CRE mice using a battery of behavioral tests. We showed that CRE mice exhibited hyperactive behavior combined with attention-deficit, sleep disturbance and impulsivity that affect their learning and memorization performances. These mice may therefore serve as a model to study attention deficit / hyperactivity disorder. Our work also pointed out the need for proper behavioral analysis of control groups in transgenic animal generation to avoid misinterpretation and misattribution of behavioral traits.