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Hyperserotonemia and Autism: The Role of 5HT Related Genes

According to the present state of knowledge, the cause of autism involves multiple genes, interacting with each other and with environmental factors to lead to the alterations in early brain development. Several lines of evidence indicate that the alterations in the 5HT neurotransmitter system might represent one of the biological substrates of autism. 5HT plays an important role in neurogenesis by controlling growth and maturation of target regions and its own neurons, pharmacological manipulation of 5HT transmission influences autistic symptoms, functional studies have shown alterations in brain 5HT synthesis capacity, while elevated 5HT levels in blood have been consistently found in about 30% of the patients. The mechanisms that lead to hyperserotonemia, the relationship between high blood 5HT level and 5HT dysfunction in the central nervous system, and its effect on the development of autism are still not understood. With the current project “Neurobiological basis of autism: The role of serotonin system”, we have been trying to unravel the nature of the relationship between hyperserotonemia and autism. A group of hyperserotonemic (HS) individuals was identified in a population of adult autistic subjects of Croatian origin. Despite the significantly higher mean 5-HT concentration in platelets of HS subjects compared to normoserotonemic (NS) and control (C) subjects, mean velocities of 5-HT uptake did not significantly differ among the groups. Significant elevations in the mean velocities of MAO B kinetics were observed in NS subjects, and were even more pronounced in HS subjects, in comparison to controls. A decrease in ADP-induced platelet aggregation was observed in NS subjects, compared to C and HS subjects. 5HTT and 5HT2Ar genotypes did not have significant influence on platelet 5HT concentrations. Significantly higher mean platelet 5HT concentrations were observed in subjects with "cc" genotype of a218c TPH and subjects with "4" genotype of uVNTR MAOA, with possible synergistic effect of the two genes. There were no significant differences in the distribution of alleles and genotypes of the TPH, MAO and 5HTT polymorphisms between autistic and control subjects. However, significantly higher incidence of G allele and GG genotype of the 5HT2Ar polymorphism was observed in the autistic group. Our results do not support the idea of 5HTT as a major contributing factor to hyperserotonemia and autism but rather suggest a possibility of upregulation of monoaminergic metabolism and, probably consequential, downregulation of 5HT2A receptor in autistic subjects.

autism; hyperserotonemia; serotonin; platelet aggregation; serotonin transporter; monoamin oxidases; tryptophan hydroxylase; 5-HT2a receptor

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