The serotonin transporter (SERT)
From The Genes of PTSD
Contents |
SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, SEROTONIN), MEMBER 4; SLC6A4
SEROTONIN TRANSPORTER; SERT 5-@HYDROXYTRYPTAMINE TRANSPORTER; 5-HTT HTT
Links to External Resources
- OMIM
- GENECARD
- Gene map locus: 17q11.1-q12
- RefSeq
Background
The serotonin transporter (SERT) plays an important role in regulating serotonin (5HT) levels in the brain by transporting 5HT from the extracellular space into the neuron. A 44–base pair polymorphism in the transcriptional control region upstream of the coding sequence of the SLC6A4 SERT gene (5HT transporter-linked polymorphic region; 5HTTLPR) results in short (SERT-s) and long (SERT-l) alleles.
Other SERT variants
There are additional SNP and deletion variants in coding and non-coding regions of SERT that are not as well characterized as 5HTTLPR at this time. For a more complete description of other variants see OMIM and [1]. One of these is a A>G substitution within 5HTTLPR. Data from in vitro studies indicates that this SNP makes the “Lg” allele act similar to an “S” allele - ie, it reduces protein expression. This observation has led to the common practice of pooling “Lg” alleles into the “S” category, the so-called “triallelic classification”, compared to the biallic classification that ignores this SNP. While the common assumption is that the tri-allelic re-classification is more biologically relevant and therefore should be utilized in psychiatric studies, the re-classification assumes that the major effect of 5HTTLPR is to alter protein levels (as in the in vitro studies). This may not be the case for other SERT biological mechanisms playing a role in the effect of SERT on human brain. In other words, while the Lg allele may alter SERT expression, it might have no effect on developmental staging (see below). Use of the triallelic re-classification should be carefully scrutinized. Examples: In a study of 5HTTLPR on social anxiety disorder, Stein et al. (2007) find a better fit with the biallelic vs the triallelic classification [1]. Re-analyzing published data on biallelic SERT effects on thalamic volume and neuron number [1] did not provide any evidence that the triallelic reclassification improved fit of the data (unpublished data, Root cause of PTSD Project).
5HTTLPR
5HTTLPR may influence protein expression
The promotor region variation appears to affect the control of transcription of SERT in vitro and does not appear to affect the structure and functionality of the transcribed protein [1] [1]. Cell culture and other in vitro studies indicate the possibility of reduced expression of SERT associated with the short allele. This potential effect of the short allele has been difficult to demonstrate in the human brain, either because there is a difference between transcriptional control of SERT in living vs in intro transcriptional control in human brain, or because of compensatory processes that normalize SERT levels despite the presence of reduced transcription. Another possibility is that SERT transcription is indeed reduced and we just can’t measure SERT accurately enough in living human brain yet to see it. Low expression of SERT may elevate serotonin levels, as demonstrated in SERT knockout mice, which have high levels of extracellular serotonin throughout life. Since serotonin is important in the developing nervous system [1], the altered levels may affect brain development, or alternatively, reduce the pool of serotonin available for release in adults.
5HTTPLR may influence developmental staging
A possibility that has not been fully explored is that the SERT-short allele could be involved in the timing of developmental alterations in SERT expression. SERT pops up in some strange places developmentally, such as being transiently expressed on certain glutamate neurons. Thalamocortical axons, which cannot synthesize serotonin, express SERT prenatally in both rodents and humans, and this expression probably functions to pump serotonin from the subcortex to the cortex during a period when the serotonin innervation of the cortex is immature, or to sites where high levels of serotonin are needed for normal development [1] [1] [1].
5HTTLPR-S accentuates limbic activity
Inheritance of the SERT-s allele has been associated with a heightened response of the limbic system to emotional stimuli [1] [1], elevated levels of subclinical depressive symptoms [1], and an increased incidence of major depression and suicidal behavior [1] [1]. In addition, 5HTTLPR genetic variants have been associated with a variety of emotion-related behaviors and conditions, including shyness, aggression, anxiety, bipolar disorder, autism, and attention-deficit/ hyperactivity disorder [1] [1] [1] [1] [1] [1]. In non-human primates, the 5HTTLPR-l allele is associated with reduced mother-child emotional attachment [1], suggesting that this allele may reduce rewarding emotional responses. The most commonly held scientific opinion is that SERT-s reduces expression of SERT protein and alters the levels of serotonin, affect neurotransmission. Since SSRI’s dramatically elevate SERT expression, they may normalize behavioral problems by normalizing neurotransmission.
5HTTLPR alters brain anatomy
An alternative hypothesis is that 5HTTLPR induces structural changes in the brain. In a recent study, Pezawas and colleagues (2005) found that normal, non-psychiatric SERT-s carriers have a 25% reduction in the volume of the anterior cingulate cortex and a 15% reduction in the volume of the amygdala[1]. In addition to reduced volumes, the study identified functional alterations in limbic circuits in SERT-s carriers (Ie, limbic hyper-responsiveness). Enlargement of thalamic nuclei (volume and neuron number) have also been observed in SERT-ss, particularly the pulvinar[1]. These data are compelling because the pulvinar, anterior cingulate cortex and amygdala are intimately involved in the processing of emotional responses and fear, and identification of anatomical changes in these limbic circuits raises the possibility that SERT-s carriers possess a unique brain structural phenotype predisposing them to depression and PTSD.
5HTTLPR x environment interaction in depression
5HTTLPR has been identified as a genetic variant that is affected by environment interactions. For both depression and PTSD, various stressors (developmental, pre and post-trauma) accentuate the effect of the S allele on diagnostic outcome and symptom severity. Caspi et al., 2003 found that developmental trauma in SS subjects elevated levels of depression in adults[1]. LL subjects tended to be resistant to depression throughout life, and SS subjects without trauma and stress had similar levels of depression compared to LL subjects. SS subjects subjected to developmental stress had 3X the level of depression and suicidality than the SS subjects without such stress. Gene x environment effects on SERT have been replicated by several studies[1], although there have been some non-replications.
PTSD
In a relatively small study, Murtza et al., 2005 found that PTSD subjects from India overexpress SERT-s by about 10% [1]. This is similar in magnitude to the overexpression of SERT-ss observed with Major Depression. Notice that the effect is driven by increased incidence of SS genotype in the PTSD group.
Control PTSD 5HTTLPR N (%) N (%) LL 21 31.34 15 22.39 LS 33 49.25 32 47.76 SS 13 19.41 20 29.85
In a larger study, Lee et al 2005 found a similar pattern of SS loading in Asian heritage PTSD subjects (Korea) [1]. Notice the high prevalence of S individuals and the low prevalence of L in this population. Studies of SERT that sample Asian heritage subjects should be carefully stratified by genetic heritage.
Control PTSD 5HTTLPR N (%) N (%) LL 7 4 2 2 LS 61 31 21 21 SS 129 65 77 77
5HTTLPR x environment interaction in PTSD
In a study of hurricane survivors, Kilpatrick et al., 2007 found that SS subjects were more likely to develop PTSD, especially if they experienced lack of social support after the trauma[1]. The data show that high risk individuals (SS or SL + low social support + high exposure) had elevated levels of PTSD compared to all other subjects. A similar interaction for Major Depression was also identified. This study supports the concept that there are significant gene x environment (stress) interactions that affect both PTSD and Depression. SERT appears to be gene of interest for both conditions, supporting evidence of strong co-morbidity between PTSD and depression and for commonalities of inheritance [1].
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