Serotonin-transporter polymorphism modulates anterior cingulate cortex activation during working memory tasks – an fMRI study

Serotonergic influences on anterior cingulate cortex (ACC) functions have been described. In addition, functional polymorphisms in the promoter region of the serotonin transporter gene 5-HTTLPR are associated with increased vulnerability for major depressive disorder (MDD). Here we investigated whether 5-HTTLPR risk variants are related to abnormalities in ACC function observed in MDD, i.e. overactivation of the ACC during the performance of a working-memory task. Fifty-six healthy subjects and remitted MDD patients were investigated with a verbal n-back task using functional magnetic resonance imaging at 3 Tesla. The impact of genotype and group were analyzed in a full-factorial design. Carriers of risk variants and remitted MDD patients revealed ACC hyperactivation. The effect of genotype remained significant for healthy participants alone. Presence of MDD and presence of 5HTTLPR risk variants are associated with ACC dysregulation during the performance of a working-memory task. In healthy participants, presence of risk variants leads to a pattern of hyperactivation similar to overactivation in MDD, indicating that 5HTTLPR effects on ACC function may mediate vulnerability to depression.