SERT polymorphisms and human cortical 5-HT2A receptors

The neurotransmitter serotonin (5-HT) is involved in a wide variety of brain functions including medical and psychiatric illnesses. Common variations in the promoter region of the gene encoding the 5-HT transporter (5-HTT; SERT) are associated with altered functional expression of the transporter. Specifically, a well-established 44 base pair deletion polymorphism in this region (termed S, for short) leads to reduced expression of transporter versus a 44 base pair insertion polymorphism in this region (termed L, for long).  Emerging evidence suggests that this system is actually tri-allelic, with highest levels of in vitro 5-HTT (SERT) expression present in the L-A L-A homozygote.

Several reports have identified associations between a given allele pattern and psychiatric conditions, including stress-associated depression. Further, robust effects of variations in the 5-HTTLPR have been demonstrated with assays of regional brain activation. However, the mechanism through which altered 5-HTT (SERT) expression is linked to stress-associated depression and altered brain function is unknown. The actions of 5-HT in the brain suggest that altered synaptic 5-HT signaling could have neurodevelopmental and ongoing structural and neurophysiological effects. Because the 5-HTT (SERT) is one regulator of the duration of serotonergic signaling, lower levels of functional expression of the axon terminal 5-HTT (SERT) (as found in the SS homozygote) predict sustained agonist effects at post-synaptic brain serotonergic receptors.

While a variety of candidate mechanisms potentially linking 5-HTTLPR polymorphisms to psychiatric illness and brain function require investigation, as our primary aim, we have chosen to use positron emission tomography (PET) employing the 5-HT receptor ligand [18 F] setoperone to examine the status of cortical 5-HT2A receptors in healthy female subjects homozygous for the SS or L-A L-A alleles of the 5-HTT promoter region polymorphism. As a secondary aim, we propose to additionally perform genotyping for T102C, a common single nucleotide polymorphism (SNP) affecting 5-HT2A expression and to examine potential brain volumetric effects of the 5-HTTLPR using the voxel-based morphometry (VBM) method to examine regional brain volume by genotype. Because the rate of depression is greater in females than males, and because regulation of the 5-HT2A receptor is influenced by estrogen, we have chosen to study the effects of having SS or L-A L-A genotype in female subjects.