Hyperserotonemia in Autism: 5HT-Regulating Proteins

Abstract

Serotonin (5-hydroxytryptamine, 5HT) is a biologically active molecule with many physiological functions in the mammalian organism. 5HT is present both in the brain (central 5HT compartment) and peripheral tissues (peripheral 5HT compartment), in which its synthesis, degradation and action is regulated by specific enzymes, transporters and receptors called 5HT-regulating proteins. Several lines of evidence indicate the involvement of serotonin in the development of autism. First, serotonin regulates many essential functions which are often disturbed in autistic subjects. Second, brain imaging studies have suggested alterations of 5HT synthesis in the brains of autistic children. Third, drugs targeting 5HT-regulating elements efficiently alleviate certain autistic symptoms. Fourth, autism is considered a neurodevelopmental disorder and serotonin has an important role in brain development. Finally, elevated 5HT levels in blood, called hyperserotonemia, have been consistently found in about 30% of patients. The mechanisms that lead to increased blood 5HT concentrations, the relationship between high blood 5HT levels and 5HT dysfunction in the central nervous system, and the role of hyperserotonemia in the development of autism are still not understood but they seem to involve alterations in 5HT-regulating proteins. According to one theory, alterations in peripheral 5HT-regulating proteins can lead to increased 5HT concentrations in the peripheral compartment. During brain development, these high 5HT levels present in blood could reach the central 5HT compartment, inhibit development of 5HT neurons and lead to the anatomical and functional alterations of the brain, characteristic for autism. According to another theory, alterations in the 5HT elements occur simultaneously in both compartments; those in the central compartment affect early brain development resulting in autistic behavioral symptoms, while those in the peripheral compartment are reflected as hyperserotonemia. Most research on the dysregulation of the 5HT system in hyperserotonemia and autism has focused on the peripheral 5HT-regulating proteins which influence the level of 5HT synthesis in the intestine, 5HT release from the intestine into blood plasma, 5HT uptake from blood plasma into platelets, 5HT release from platelets, and 5HT degradation in liver and lungs. The research conducted so far indicates increased 5HT metabolism (i.e. synthesis and degradation), increased accumulation (uptake)…