Altered inflammatory responsiveness in serotonin transporter mutant rats
Growing evidence suggests that alterations of the inflammatory/immune system contribute to the pathogenesis of depression. Indeed, depressed patients exhibit increased levels of inflammatory markers in both the periphery and the brain, and high comorbidity exists between major depression and diseases associated with inflammatory alterations. In order to characterize the link between depression and inflammation, we aimed to investigate whether an altered inflammatory system is present in a genetic model of vulnerability for depression, namely rats with partial or total deletion of the serotonin transporter (SERT) gene.
Wild-type, heterozygous and homozygous SERT rats were analyzed under basal condition or following a challenge with an acute injection of lipopolysaccharide (LPS) and killed 24 h or 5 days later.
We found that SERT mutant rats show altered cytokine expression in the dorsal and ventral hippocampus at basal conditions, and they also display an exacerbated cytokine response to the LPS challenge. Moreover, mutant rats exhibit differences in the expression of markers for microglia activation.
Based on these data, we suggest that basal or functional alterations of immune/inflammatory systems might contribute to the phenotype of SERT rats and to their heightened susceptibility to depressive-like behavior.
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“In conclusion, our results demonstrate that the inflammatory/immune system is altered in rats with genetic alterations of the serotonin transporter.
Moreover, these animals show a different response to an inflammatory challenge, suggesting that some of the mechanisms that regulate these systems can be compromised, thus rendering the hippocampus more susceptible to the adverse influence of inflammatory mediators.
Since depression vulnerability can be associated with increased inflammation, we suggest that the alterations of the immune system observed in animals with a deletion of the SERT gene may contribute to their pathologic phenotype.
Furthermore, considering that depressed patients with higher levels of cytokines, as well as individuals carrying the S variant of the 5-HTTLPR polymorphism, are less responsive to antidepressant treatment [53,54], we may speculate that alterations of the immune/inflammatory system in depressed individuals may not only contribute to the pathologic phenotype, but also represent an important component for the response to