Polymorphisms in the 3' UTR of the serotonin transporter are associated with cognitive flexibility in rhesus macaques.

The serotonin system is an important neurophysiological mediator of many behavioral phenotypes. Genetic variation within this system is thought to contribute not only to the natural range of behavioral differences, but also to neuropsychiatric pathologies. Cognitive flexibility, the ability to change patterns of response as reward context shifts, is an important trait that underlies many complex social interactions. Environmental manipulations of the serotonin system have been shown to alter performance on tests measuring cognitive flexibility. Variation at the serotonin transporter promoter region (5HTTLPR) has recently been shown to associate with the performance of rhesus monkeys on an object discrimination reversal learning task [Izquierdo et al., 2007]. Here, we demonstrate that functional genetic variation at the serotonin transporter 3' untranslated region, independent of 5HTTLPR, also associates with performance in an object discrimination reversal learning task in rhesus macaques. The polymorphisms comprising the T:G:T haplotype (T1970, G1991, and T2327) were associated with fewer errors on a reversal learning test and greater levels of cognitive flexibility. We have previously demonstrated that the T:G:T haplotype renders lower levels of gene expression in vitro, paralleling the functionality of human 3' UTR haplotypes, as well as the short allele of 5HTTLPR found in both macaques and humans. The 3' UTR haplotypes are independent and in linkage equilibrium with the 5HTTLPR locus. Together, these data lead to the intriguing possibility that differences observed in human cognitive flexibility, whether naturally or in pathological states, may be associated with genetic variation in the serotonin transporter 3' untranslated region also.