Cortisol and SERT expression
As excess cortisol is associated with many serotonin-derived pathological conditions, its role in altering serotonin function should be investigated. Certainly, evidence is emerging for an effect of cortisol on SERT expression in cells and tissue. Dexamethasone, a synthetic glucocorticoid, has been demonstrated to increase the mRNA and protein expression of SERT in immortalized human B-lymphoblastoid cells [241], an effect that was dependent on a region located 1.4 kb upstream of the 5HTT gene transcription site and was elevated in both polymorphisms of the 5-HTTLPR promoter sequence. Stress and elevated cortisol has been demonstrated to elevate tissue SERT expression in rodent and human studies [242-244]. In a rodent model, maternal administration of dexamethasone during gestation produced persistent increases in (3H+) paroxetine (SSRI) binding to SERT in the brainstem and cortex without affecting the numbers of serotonergic nerve terminals [245]. Interestingly, alterations in brain serotonin levels were not offset by changes in the fractional serotonin turnover rate [246].
Both forms of the 5-HTTLPR promoter sequence polymorphisms have been reported to be associated with ASD [113-118]. However, neither polymorphism in the promoter sequence has been demonstrated conclusively to be associated with ASD. Similarly, allelic variants within the 5-HTTLPR, have been reported, which indicates that variants within the S and L alleles occur. These variants have been investigated in a Caucasian and Japanese population, demonstrating significant ethnic differences for the distribution of alleles and genotypes [247]. However, common polymorphism/s in the 5-HTTLPR promoter sequence that confers increased subsceptibility to elevated cortisol levels in the GR, GRE or coactivator sites, should be considered as a focus of genetic studies. The GRE consensus sequence, the hexanucleotide TGTTCT, was originally proposed, however, further evidence has indicated that the GRE can involve an imperfect inverted repeat of the hexanucleotide TGTTCT with a 3-bp spacer to create a palindromic structure [248]. The GRE is very similar in nucleotide sequence to the oestrogen response element (ERE) where minor changes in base sequence for the ERE can be converted to a GRE [249,250]. Changes in the nucleotide sequence can also confer altered sensitivity to GR-induced function [249,250]. Furthermore, the GR interaction with the palindromic site promotes an allosteric change in the DNA-binding domain, to alter the protein shape and promote dimerization with a second GR monomer subunit [248]. Mutations in the GR DNA-binding domain (Ser459Ala) and D loop (Pro493Arg) causes the formation of a constitutive dimerization interface, inducing GR dimerization on a non-specific DNA [251]. Other SNPs in the GR, including ER22/23EK, N363S and BcII have been found to be associated with glucocorticoid sensitivity and stress-induced cortisol responses, and provide potential targets for investigating the genetic inheritance of ASD [252].