SERT Models of Emotional Dysregulation

The serotonin system plays a key modulatory role in central nervous system processes that appear to be dysregulated in psychiatric disorders. Specifically, the serotonin transporter (SERT) is thought to be critical to many aspects of emotional dysregulation, and has been a successful target for medications that treat several psychiatric disorders. Here, we narrowly focused on two psychiatric conditions, anxiety and depression, for which mice with SERT genetic manipulations has provided insight. Specifically, we suggest that dissecting syndromes according to a trait and state perspective may help us understand the complex and at times contradictory rodent results. The most compelling reason for this approach is provided by human studies in which increased trait neuroticism and stressmediated vulnerability to develop depression were reported for subjects carrying the 5HTTLPR s/s allele of the SERT gene, thus placing the contribution of SERT to mood disorders in a gene x environment and trait/state context. Accordingly, current behavioral results in SERT KO mice are consistent with both increased trait and state anxiety-like behaviors, while evidence in support of a trait-based model of depression in SERT KO mice are inconsistent and mostly based on tests with limited relevance to human depression. However, comorbid symptoms associated with a wider definition of depression, such as altered gastrointestinal functions, lower pain threshold, and greater sensitivity to stress, have been reported in SERT KO mice, suggesting the presence of a prodepressive state resulting from low SERT. Studies on SERT mutant mice, as putative genetic models of increased vulnerability to develop a depressive state in response to chronic challenges (i.e. paralleling the s-allele mediated vulnerability in humans), have only begun. Finally, studies will need to integrate trait/state features with gender specific approaches to fully recapitulate the risk factors that are known to influence the vulnerability to develop altered mood regulation in human subjects, namely genetic load, sex and environment. To this end, SERT mutant mice can provide a critical window into mechanisms leading to increased risk for mood disorders, with the potential to reveal new targets for antidepressant drug development.