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 involving 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.

Figure 1. Serotonin: Modulatory involvement in Complex Quantitative Traits and Complex Disorders

Figure 2. Human SERT Gene Organization, with Multiple Functional Variants

Figure 3. Potential Five-Fold Range of SERT Expression/Function Related to Common Plus Rare Human SLC6A4 Gene Variants

Figure 4. Comparison of serotonin-transporter (SERT) expression and function in Slc6a4-mutant mice and in humans with different SLC6A4 5-HTTLPR genotypes

Figure 5. Increased Cocaine Preference in SERT +/+, +/- and -/- Mice and Consequent Decreased Cocaine Preference in these Mice Cross-Bred with Dopamine Transporter (DAT)-Deficient Mice

Figure 6. Comparisons of SERT-Deficient vs. SERT Over-Expressing Mice: ECF Serotonin Concentration Differences

Figure 7. Serotonin Clearance Rates and ECF Serotonin Measurements in SERT-Deficient Mice

Figure 8. Comparison of Serotonin Dynamic Homeostasis in SERT +/+ vs. SERT -/- Mice

Figure 9. Tissue Serotonin Reductions in the Periphery and in Five Brain Regions of SERT -/- Mice

Figure 10. Differential Expression of SERT in SERT +/+, +/- and -/- Mice and Comparison to mC-DASB Binding in Human Brain

Figure 11. Comparisons of SERT-Deficient vs. SERT Over-Expressing Mice: SERT Binding Sites and Anxiety-Like Behavioral Differences

Figure 12. Absent or Attenuated 5-HT_1A - Mediated Raphe 5-HT Neuron Firing Rate and Temperature Responses to the 5-HT_1A Agonist, 8-OH-DPAT

Figure 13. Attenuation of Post-Receptor Signaling via PLA2 and ³H-Arachidonic Acid Induced by the HTR_2A Receptor Agonist DOI, Accompanied by a Reduction in the Head Twitch Response to DOI

Figure 14. Acoustic Startle, Plasma ACTH and Plasma and Adrenal Gland Epinephrine Responses to Stress in SERT-Deficient Mice

Figure 15. Whisker Barrel Disruption in Layer IV Somatosensory Cortex of SERT Mutant Mice, Compared To Findings in Studies of Other Mutant Mice

Figure 16. SERT -/- Mice Show Reduced Local Cerebral Glucose Utilization in Whisker-to-Barrel Pathway in Response to Unilateral Vibrissal Stimulation

Figure 17. Exaggerated Serotonin Syndrome Responses to 5-HTP and to Tranylcypromine In SERT-Deficient Mice

Figure 18. Return of Depression and OCD Symptoms After Treatment Discontinuation In Recovered Patients (Mean Rating Changes in 18 Patients with Obsessive-Compulsive Disorder Before And During Double-Blind Discontinuation of Clomipramine, with Placebo Substitution)

Figure 19. SERT 5HTTLPR Predicts Treatment Discontinuation Due to Adverse Effects Among 246 Depressed Patients, with SS Patients Showing Higher Discontinuation Rates

Figure 20. Central and Peripheral Serotonergic Systems

Serotonin also functions in the enteric nervous system (ENS), the hypothalamo-pituitary-adrenocortical (HPA) system, the adrenomedullary neuroendocrine serotonin system (NSS) and the peripheral serotonin system (PSS), which includes the lungs, the heart, the blood vessels, the pancreas and platelets DRN, dorsal raphe nucleus; MFB, medial frontal bundle; MRN, median raphe nucleus.

Figure 21. Evolutionary Relatedness and Sequence Comparison of SERT from Several Species: lle425 and Gly56 are Highly Conserved Across >8 of 10 Species

Figure 22. Bacterial LeuT Homology Model for hSERT

(A) The first high resolution transporter structure resolved: bacterial LeuT (20); (B) homology model of hSERT, with lleu425 on TM8. (C, D, E, F) location of other hSERT variants described recently. TM4 (Leu255Met, TM5 (Ser293Phe); TM6 Pro339Leu); TM7 (Leu362Met) 99 (Sing S, personal communication, March, 2007).

Figure 23. SERT and Other Putative Serotonin-Related Pharmacogenetic Interactions in Humans and Mice

Genes studied include SLC6A4 (SERT), Environmenral Factors include traumetic life events (TLE). Other medications such as Monoamine Oxidase Inhibitor (MAOI), Tryptophan (TP), 5-hydroxytryptophan (5-HTP), Lysergic Acid (LSD), Methylenedioxymethamphetamine (MDMA), which can lead to the serotonin syndrome (S/S).

Figure 24. Metanalysis of Ten Studies Examining Antidepressant Responses to SRIs and SERT 5HTTLPR Polymorphism

Figure 25. Lack of Behavioral Immobility Response to Fluoxetine in SERT -/- Mice (C57BL/6J background), but Intact or Exaggerated Responses to Tricyclic Antidepressants

Figure 26. Antidepressant Response and Side Effects: Associations with SERT 5HTTLPR

Figure 27. Phenotypical Consequences of the Targeted Disruption of SERT in the Mouse