Abnormal anxiety‐related behavior in serotonin transporter null mutant mice: the influence of genetic background

Serotonin transporter (5‐HTT) null mutant mice provide a model system to study the role genetic variation in the 5‐HTT plays in the regulation of emotion. Anxiety‐like behaviors were assessed in 5‐HTT null mutants with the mutation placed on either a B6 congenic or a 129S6 congenic background. Replicating previous findings, B6 congenic 5‐HTT null mutants exhibited increased anxiety‐like behavior and reduced exploratory locomotion on the light ↔ dark exploration and elevated plus‐maze tests. In contrast, 129S6 congenic 5‐HTT null mutant mice showed no phenotypic abnormalities on either test. 5‐HTT null mutants on the 129S6 background showed reduced 5‐HT 1A receptor binding (as measured by quantitative autoradiography) and reduced 5‐HT 1A receptor function (as measured by 8‐OH‐DPAT‐indcued hypothermia). These data confirm that the 5‐HTT null mutation produced alterations in brain 5‐HT function in mice on the 129S6 background, thereby discounting the possibility that the absence of an abnormal anxiety‐like phenotype in these mice was due to a suppression of the mutation by 129 modifier genes. Anxiety‐like behaviors in the light ↔ dark exploration and elevated plus‐maze tests were significantly higher in 129S6 congenic +/+ mice as compared to B6 congenic +/+ mice. This suggests that high baseline anxiety‐like behavior in the 129S6 strain might have precluded detection of the anxiety‐like effects of the 5‐HTT null mutation on this background. Present findings provide further evidence linking genetic variation in the 5‐HTT to abnormalities in mood and anxiety. Furthermore, these data highlight the utility of conducting behavioral phenotyping of mutant mice on multiple genetic backgrounds.