engleski

Hyperserotonemia in autism: activity of proteins that regulate platelet 5HT concentrations

Serotonin (5HT) concentrations in blood platelets are regulated through the action of several proteins: tryptophan hydroxylase that mediates 5HT synthesis, serotonin transporter that mediates 5HT accumulation in platelets, 5HT2A receptor that mediates 5HT release during platelet aggregation, and monoamine oxydase (MAO) that mediates 5HT degradation. Elevated 5HT concentrations in blood, called hyperserotonemia, have been consistently found in about one third of subjects suffering from autism &#8211; a neurodevelopmental disorder characterized by social and communication dysfunction and stereotypic behaviors. Cause of hyperserotonemia and its relation to the serotonergic dysfunction in brain are still unknown, but it might lie in altered expression/function of one or more of the above mentioned proteins. In this study, we have measured the activity of 5HT transporter, MAO B and 5HT2A receptor in platelets of 16 hyperserotonemic (HS), 16 normoserotonemic (NS) and 15 healthy control (C) subjects. Platelet rich plasma was obtained from anticoagulated venous blood and aliquoted for the analysis. 5HT concentration was measured by orthophtaldialdehyde-enhanced fluorometry. Velocity of 5HT transport across the platelet membrane was measured by radioisotopic method using 14C-5HT as a substrate. Velocity of MAO B kinetics was measured fluorometrically using kynuramine as a substrate. Results were expressed per total platelet volume, calculated as a product of mean platelet volume and platelet number (determined by cell counter). 5HT2A receptor-mediated aggregation was measured in whole blood by platelet aggregometry using adenosine diphosphate (ADP) as agonist. Despite the significantly higher mean 5HT concentration in platelets of HS subjects compared to NS and C subjects (p<0.001), mean velocities of 5HT uptake did not significantly differ among the groups (p=0.432). On the other hand, significant elevations in the mean velocities of MAO B kinetics were observed in NS subjects (p<0.01), and were even more pronounced in HS (p<0.001) subjects, in comparison to controls. Also, a decrease in ADP-induced platelet aggregation of borderline significance (p<0.05) was observed in NS subjects, compared to C subjects. The results indicate upregulation in MAO B activity and decreased number/sensitivity of 5HT2A receptors in platelets of autistic subjects. It seems that the mentioned alterations are related to autistic disorder per se, while their extent is modified by serotonemic status.

autism; serotonin; 5HT transporter; monoamine oxydase; 5HT2A receptor; hyperserotonemia

Rad je kao poster prezentitiran na skupu 50 godina molekularne biologije u Hrvatskoj, održanom od 20.-21.11.2008., Zagreb, Hrvatska i objavljen uz domacu recenziju u Zborniku sažetaka ; Zagreb : Institut Ruđer Bošković, 2008. ; str. 123-123 (ISBN 978-953-6690-78-7).