Genetically dependent modulation of serotonergic inactivation in the human prefrontal cortex

Previous research suggests that genetic variations regulating serotonergic neurotransmission mediate individual differences in the neural network underlying impulsive and aggressive behaviour. Although with conflicting findings, the monoamine oxidase-A (MAOA) and the serotonin transporter (5HTT) gene polymorphisms have been associated with an increased risk to develop impulsive and aggressive behaviour. Double knock-out mice studies have also demonstrated that MAOA and 5HTT genes strongly interact in the metabolic pathway leading to the serotonergic inactivation; however, their potential interactive effect in human brain remains uninvestigated. We used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to assess the independent and interactive effects of both MAOA and 5HTT polymorphisms on the brain activity elicited by a response inhibition task in healthy volunteers. Multivariate analysis demonstrated an individual effect of both MAOA and 5HTT polymorphisms and a strong allele-allele interaction in the anterior cingulate cortex (ACC), a key region implicated in cognitive control and in the pathophysiology of impulsive and aggressive behaviour. These findings suggest that the MAOAx5HTT allelic interaction exerts a significant modulation on the BOLD response associated with response inhibition and contribute to validate haplotype models as useful tools for a better understanding of the neurobiology underlying complex cognitive functions.