Behavioral phenotypes of knockout mice are often interpreted as the effects of the absence of the gene product on adult behavior, yet behavioral differences among genotypes may be exaggerated or blurred by the postnatal environment. For example, mice develop in litters of varying sex ratios and genotypes, and it is possible that some of these behavioral differences may result from the composition of the litter. To determine whether these factors might play a role in the development of the behavioral characteristics that have become diagnostic of the knockout, offspring of parents heterozygous for a null mutation of estrogen receptor α (ERKO) were sexed and genotyped within 2 days of birth. Litters were then reconstituted, forming same-sex litters of equal numbers of ERKO and wild-type (WT) individuals that were tested in a standard resident-intruder paradigm. In this manner the effect of genotype would be evident without the potential confound of the presence of the opposite sex in the litter. Behavioral differences between the genotypes were more sharply defined than reported previously. ERKO females displayed only aggressive behavior whereas their WT littermates displayed only mounting behavior; both aggression and mounting behavior were greatly reduced in ERKO males. These data suggest that the postnatal environment such as litter composition may influence the development of sociosexual behaviors in ERKO mice.
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