Abstract
The human serotonin transporter (SERT) gene possesses a 43-base pair (bp) insertion-deletion promoter polymorphism, the h5-HTTLPR. Genotype at this locus correlates with variation in anxiety-related personality traits and risk for major depressive disorder in many studies. Yet, the complex effects of the h5-HTTLPR, in combination with closely associated single-nucleotide polymorphisms (SNPs), continue to be debated. Moreover, although SERT is of high clinical significance, transporter function in vivo remains difficult to assess. Rhesus express a promoter polymorphism related to the h5-HTTLPR. The rh5-HTTLPR has been linked to differences in stress-related behavior and cognitive flexibility, although allelic variations in serotonin uptake have not been investigated. We studied the serotonin system as it relates to the 5-HTTLPR in rhesus peripheral blood cells. Sequencing of the rh5-HTTLPR revealed a 23-bp insertion, which is somewhat longer than originally reported. Consistent with previous reports, no SNPs in the rh5-HTTLPR and surrounding genomic regions were detected in the individuals studied. Reductions in serotonin uptake rates, cell surface SERT binding, and 5-hydroxyindoleacetic acid/serotonin ratios, but not SERT mRNA levels, were associated with the rh5-HTTLPR short allele. Thus, serotonin uptake rates are differentiable with respect to the 5-HTTLPR in an easily accessible native peripheral tissue. In light of these findings, we foresee that primary blood cells, in combination with high sensitivity functional measurements enabled by chronoamperometry, will be important for investigating alterations in serotonin uptake associated with genetic variability and antidepressant responsiveness in humans.
Highlights
A number of polymorphisms in human genes coding for key proteins that regulate serotonin (5-HT) neurotransmission have been discovered
The human 5-HTTLPR is postulated to drive allele-specific serotonin transporter gene (SERT) promoter activity leading to differences in mRNA and protein levels, and functional serotonin uptake (Figure 1).[1]
We investigated each of these aspects of SERT expression and function, in addition to serotonin and 5-hydroxyindoleacetic acid (5-HIAA) concentrations, to elucidate the effects of the rh5-HTTLPR in native PBCs
Summary
A number of polymorphisms in human genes coding for key proteins that regulate serotonin (5-HT) neurotransmission have been discovered. Among these are functional polymorphisms in the transcriptional control and noncoding regions of the serotonin transporter gene (SERT; SLC6A4).[1,2,3,4] A 43-base pair (bp) insertion/deletion polymorphism in the promoter region of the human SERT gene, termed the 5-HT transporter-linked polymorphic region (h5-HTTLPR; Figure 1), has received considerable attention owing to its purported relationship with anxietyrelated personality traits,[5,6,7] stress-associated depression,[8,9] amygdala activation in response to negative stimuli,[10,11] and suicide.[12].
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