How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems

Abstract

Discovered and crystallized over sixty years ago, serotonin's important functions in the brain and body were identified over the ensuing years by neurochemical, physiological and pharmacological investigations. This 2008 M. Rapport Memorial Serotonin Review focuses on some of the most recent discoveries in serotonin that are based on genetic methodologies. These include examples of the consequences that result from direct serotonergic gene manipulation (gene deletion or overexpression) in mice and other species; an evaluation of some phenotypes related to functional human serotonergic gene variants, particularly in SLC6A4, the serotonin transporter gene; and finally, a consideration of the pharmacogenomics of serotonergic drugs with respect to both their therapeutic actions and side effects. The serotonin transporter (SERT) has been the most comprehensively studied of the serotonin system molecular components, and will be the primary focus of this review. We provide in-depth examples of gene-based discoveries primarily related to SLC6A4 that have clarified serotonin's many important homeostatic functions in humans, non-human primates, mice and other species.

Conservation of gene function in behaviour

“…5-HTT encodes for a protein involved in serotonin re-uptake. Studies of this gene in non-human primates and in human populations have identified a promoter-linked polymorphic region that interacts with early experience to affect behaviours in the young and adults [23]. The long and short alleles result from a 43 bp insertion/deletion in the promoter region of the 5-HTT gene.…”

Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants

“…The serotonin transporter SERT or 5-HTT, encoded by the SLC6A4 gene, is thought to play a prominent role in serotonin homeostasis in primates and non-human primates, and several gene variants that may change the structure or function of the transporter protein were associated with autism [8]. Among them, polymorphisms within the 5-HTTLPR promoter sequence, mutations in the coding sequence, or intronic mutations of this serotonin transporter were reported to be linked to autism by some studies, but other studies have been inconclusive [8][9][10].…”

“…Among them, polymorphisms within the 5-HTTLPR promoter sequence, mutations in the coding sequence, or intronic mutations of this serotonin transporter were reported to be linked to autism by some studies, but other studies have been inconclusive [8][9][10]. The SLC6A4 5-HTTLPR promoter sequence, located about 1 kb upstream of the transcription initiation site, contains two variable repeat length polymorphisms known as the long (L) with 16 repeat elements, or the 44 bp shorter (S) variant with 14 repeat elements [11,12], which determines a different expression of the serotonin transporter in pre-synaptic axonic membranes.…”

“…Pharmacological studies of serotonin re-uptake by EBV-transformed lymphocytes expressing the heterozygous Gly56Ala or homozygous 56Ala protein mutants indicated a progressive gain of function by 1.4 or 1.8 fold, respectively, compared to cells expressing the wild-type SERT (Gly56) [15]. Another known variant of the SLC6A4 gene, which potentially modulates serotonin transport function, is a variable number of tandem repeat (VNTR) polymorphism in intron 2, STin2.9, STin2.10, and STin2.12, containing 9, 10 and 12 copies of the VNTR element, respectively [8,16].…”

Extraordinarily Fast Response to Low-Dose Sertraline in a Child with Severe Obsessive-Compulsive Disorder and High Functioning Serotonin Transporter Genotype

“…Comparison between the S-[short] and L-[long] alleles of 5-HTTLPR shows that the L-allele exerts increased transcriptional activity and increased basal reuptake of serotonin in vitro Lesch et al 1996;Murphy et al 2008). The L-allele is, therefore, referred to as the gain-of-function variant of the serotonin transporter.…”