Elsevier

Biological Psychiatry

Volume 69, Issue 6, 15 March 2011, Pages 513-519
Biological Psychiatry

Review
Looking on the Bright Side of Serotonin Transporter Gene Variation

https://doi.org/10.1016/j.biopsych.2010.09.024Get rights and content

Converging evidence indicates an association of the short (s), low-expressing variant of the repeat length polymorphism, serotonin transporter-linked polymorphic region (5-HTTLPR), in the human serotonin transporter gene (5-HTT, SERT, SLC6A4) with anxiety-related traits and increased risk for depression in interaction with psychosocial adversity across the life span. However, genetically driven deficient serotonin transporter (5-HTT) function would not have been maintained throughout evolution if it only exerted negative effects without conveying any gain of function. Here, we review recent findings that humans and nonhuman primates carrying the s variant of the 5-HTTLPR outperform subjects carrying the long allele in an array of cognitive tasks and show increased social conformity. In addition, studies in 5-HTT knockout rodents are included that provide complementary insights in the beneficial effects of the 5-HTTLPR s-allele. We postulate that hypervigilance, mediated by hyperactivity in corticolimbic structures, may be the common denominator in the anxiety-related traits and (social) cognitive superiority of s-allele carriers and that environmental conditions determine whether a response will turn out to be negative (emotional) or positive (cognitive, in conformity with the social group). Taken together, these findings urge for a conceptual change in the current deficit-oriented connotation of the 5-HTTLPR variants. In fact, these factors may counterbalance or completely offset the negative consequences of the anxiety-related traits. This notion may not only explain the modest effect size of the 5-HTTLPR and inconsistent reports but may also lead to a more refined appreciation of allelic variation in 5-HTT function.

Section snippets

5-HTTLPR and Emotionality

There is general consensus—although there are also a considerable number of replication failures—that the s-allele is associated with emotionality or stress sensitivity, as has previously been described in comprehensive reviews (2, 5, 6, 7). In summary, Hariri et al. (8), as well as others (for review, see [5]), revealed that s-allele carriers displayed relatively exaggerated reactivity in the amygdala to pictures of fearful faces. Further, s-allele carriers show increased startle responses (9

5-HTTLPR and (Social) Cognition

More recently, researchers turned their attention to the role of 5-HTTLPR in cognitive functions. In 2007, Roiser et al. (51) demonstrated that s-allele carriers showed superior performance in the affective go/no-go task, an attentional test that measures the ability to withhold an intentional motor response based on the emotional valence of words. This finding may be in accord with increased memory recall, as observed in the recall stage of the affective directed forgetting test (51). Further,

5-HTTLPR and Brain Function

Noninvasive psychophysiological and morphofunctional neuroimaging studies have provided important insights in the neural circuits that bias behavioral responses in association with the 5-HTTLPR s-allele. Kickoff for imaging of genetic variation was in 1999 when Fallgatter et al. (65) linked the s variant to increased activity of the prefrontal cortex (PFC) during a response inhibition task. In 2002, Hariri et al. (8) reported that s-allele carriers exhibited increased amygdala reactivity during

Lessons from Serotonin Transporter Knockout Rodents

Serotonin transporter knockout (5-HTT−/−) mice were generated in 1998 by deleting a critical region of the gene via homologous recombination (82). In 2007, the 5-HTT−/− rat was introduced, generated by chemical mutagenesis that resulted in a premature stop codon in the 5-HTT gene (83). Using microdialysis, it is well established that 5-HTT−/− mice and rats exhibit increased extracellular serotonin levels in various brain regions (84). This could contribute to neurodevelopmental alterations (73)

Conclusion and Outlook

Evidence accumulated from studies in humans, nonhuman primates, and rodent models suggests a link between the neurobehavioral effects of the 5-HTTLPR s-variant and hypervigilance, an enhanced sensitivity to motivationally relevant environmental stimuli (Figure 1). This hypervigilance leads to enhanced emotional responses when environmental conditions are stable or uncontrollable, that is, when there are no explicit stimuli or conditions that draw attention away from stimuli predicting adversity

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