Figure 1. Putative effects of 5-HTT gene variation on human 5-HT neurotransmission based on findings from 5-HTT knockout mice. (a) Following release of 5-HT, 5-HTT actively returns 5-HT to the presynaptic neuron and thereby determines the duration and intensity of 5-HT communication with its receptors on postsynaptic targets located in limbic regions mediating emotion. (b) A low-expressing (‘S allele’) form of the human 5-HTT gene has been associated with relatively lesser 5-HTT mRNA transcription and 5-HTT binding, and reduced platelet 5-HT reuptake 9, 10 and 11, as well as reduced 5-HT1A receptor binding in brain [61]. In mice genetically engineered without a functioning 5-HTT, loss of 5-HTT gene function increases extracellular levels of 5-HT and leads to brain region-specific reductions in 5-HT1A and 5-HT1B receptor binding and increases in 5-HT2A, 5-HT2C and 5-HT3 receptor mRNA levels and/or ligand binding 15, 16, 17, 24 and 60. Although the net effect of these complex changes is not fully understood, they might contribute to alterations in emotional processing associated with a relative loss of 5-HTT function in S allele carriers.

Figure 2. The low-expressing (S allele) 5-HTT gene variant is associated with greater amygdala reactivity in response to emotionally provocative stimuli. (a) Illustration of the greater mean right amygdala activity in S allele carriers than in L allele homozygotes (S carriers>LL). Reproduced with permission from [18]. (b) Activity of this same right amygdala region in single-subjects from both genotype groups (S carriers versus LL). Note, sample size in most studies has limited the analyses of genotype effects to S carriers (SS and LS) versus L homozygotes (LL). However, both the initial in vitro studies of the 5-HTTLPR 9 and 11, and a subsequent in vivo study [18] indicate that the S allele has a dominant effect on gene expression and amygdala activity and, thus, support this more general classification scheme.

Figure 3. A working model of how 5-HTT gene variation alters the neural circuitry regulating emotion. A low-expressing (‘S allele’) form of the human 5-HTT gene is associated with a relative exaggeration in the response of the amygdala to anxiety-provoking stimuli 18, 50, 53, 54, 55, 56, 57 and 58. S allele carriers further exhibit diminished communication between the amygdala and components of the pACC, the sub- and supragenual ACC [66], which might result in a reduced capacity for integration of arousal in the planning and execution of complex behaviors and responses to the environment. This deficit in processing emotional information may in turn manifest at the behavioral level as increased negative emotionality and stress vulnerability. Abnormalities in functional connectivity between the prefrontal cortex and amygdala during emotional processing have been independently reported in S allele carriers 53 and 66 and mutant mice lacking the 5-HTT (Wellman et al., unpublished). Thus, the integrity of this key cortico-amygdala pathway appears to be affected by genetic variation in 5-HTT function.

Figure 4. Parallel, complementary approaches to understanding the role of 5-HTT gene variation in influencing emotional regulation using neuroimaging and mutant mice. (a) Human genetic studies identified the S allele of the 5-HTTLPR as a factor associated with increased negative emotionality traits and risk for emotional disorders. Functional neuroimaging pinpointed the amygdala as a brain region with exaggerated reactivity to emotionally provocative stimuli in S allele carriers, paving the way for further research to elucidate the precise neural mechanisms underlying the behavioral abnormalities associated with this gene variant. (b) The identification of the 5-HTT as a candidate gene for abnormal emotion led to the creation of mice with a functional null gene (knockout) mutation in the 5-HTT. Phenotyping of 5-HTT knockout mice using well-validated tests demonstrated abnormal emotion-related behaviors, supporting the utility of these mice as a model for elucidating the neural mechanisms underlying the effects of 5-HTT gene variation on emotion.

Relative loss of 5-HTT gene function is associated with increased vulnerability to environmental stress across species

Imaging genetics studies of 5-HTTLPR effects on amygdala reactivity to emotionally provocative stimuli