The serotonin transporter knockout (SERT(-/-)) mouse, generated in 1998, was followed by the SERT(-/-) rat, developed in 2006. The availability of SERT(-/-) rodents creates the unique possibility to study the conservation of gene function across species. Here we summarize SERT(-/-) mouse and rat data, and discuss species (dis)similarities in neurobehavioral endophenotypes. Both SERT(-/-) rodent models show a disturbed serotonergic system, altered nociception, higher anxiety, decreased social behavior, as well as increased negative emotionality, behavioral inhibition and decision making. Used to model a wide range of psychiatric disorders, SERT(-/-) rodents may be particularly valuable in research on neurodevelopmental disorders such as depression, anxiety, and possibly autism. We conclude that SERT function is conserved across mice and rats and that their behavioral profile arises from common neurodevelopmental alterations. Because mice and rats have species-specific characteristics that confer differential research advantages, a comparison of the two models has heuristic value in understanding the mechanisms and behavioral outcome of SERT genetic variation in humans.
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