Hyperserotonemia in Autism: 5HT-Regulating Proteins

  • Dubravka HranilovicEmail author
  • Sofia Blazevic
Reference work entry


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 are 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) of 5HT into platelets, and decreased functionality of 5HT receptors (5HT2A) present on the platelet membrane. Fewer studies have been conducted on the central 5HT-regulating proteins, yet they indicate alterations in the central compartment as well. Central 5HT disturbances, although obvious, are far less clear and may involve malfunction of 5HT as both a developmental factor and neurotransmitter.

Further research on large, uniform, and diagnostically clearly defined samples should facilitate the identification of the biochemical correlates of autism, including the role of 5HT-regulating proteins.


5HT2A Receptor Central Compartment Autistic Child Presynaptic Neuron Enterochromaffin Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abramson RK, Wright HH, Carpenter R, et al. Elevated blood serotonin in autistic probands and their first-degree relatives. J Autism Dev Disord. 1989;19:397–407.PubMedCrossRefGoogle Scholar
  2. Anderson GM. Monoamines in autism: an update of neurochemical research on a pervasive developmental disorder. Med Biol. 1987;65:67–74.PubMedGoogle Scholar
  3. Anderson GM, Minderaa RB, van Benthem PP, et al. Platelet imipramine binding in autistic subjects. Psychiatry Res. 1984;11:133–41.PubMedCrossRefGoogle Scholar
  4. Anderson GM, Horne WC, Chatterjee D, et al. The hyperserotonemia of autism. Ann N Y Acad Sci. 1990;600:331.PubMedCrossRefGoogle Scholar
  5. Anderson GM, Gutknecht L, Cohen DJ, et al. Serotonin transporter promoter variants in autism: functional effects and relationship to platelet hyperserotonemia. Mol Psychiatry. 2002;7:831–6.PubMedCrossRefGoogle Scholar
  6. Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355–66.PubMedCrossRefGoogle Scholar
  7. Betancur C, Corbex M, Spielewoy C, et al. Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder. Mol Psychiatry. 2002;7:67–71.PubMedCrossRefGoogle Scholar
  8. Billett EE. Monoamine oxidase (MAO) in human peripheral tissues. Neurotoxicology. 2004;25:139–48.PubMedCrossRefGoogle Scholar
  9. Boullin DJ, Bhagavan HN, Coleman M, et al. Platelet monoamine oxidase in children with infantile autism. Med Biol. 1975;53:210–3.PubMedGoogle Scholar
  10. Brzezinski A. Melatonin in humans. N Engl J Med. 1997;336:186–95.PubMedCrossRefGoogle Scholar
  11. Bursztejn C, Ferrari P, Dreux C, et al. Metabolism of serotonin in autism in children. Encéphale. 1988;14:413–9.PubMedGoogle Scholar
  12. Campbell M, Friedman E, DeVito E. Blood serotonin in psychotic and brain damaged children. J Autism Child Schizophr. 1974;4:33–41.PubMedCrossRefGoogle Scholar
  13. Chen K, Wu HF, Shih JC. The deduced amino acid sequences of human platelet and frontal cortex monoamine oxidase B are identical. J Neurochem. 1993;61:187–90.PubMedCrossRefGoogle Scholar
  14. Chugani DC. Serotonin in autism and pediatric epilepsies. Ment Retard Dev Disabil Res. 2004;10:112–6.CrossRefGoogle Scholar
  15. Cohen DJ, Young JG. Platelet monoamine oxidase in early childhood autism. Arch Gen Psychiatry. 1977;34:534–7.PubMedCrossRefGoogle Scholar
  16. Cook EH, Leventhal BL, Heller W, et al. Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine levels and intelligence. J Neuropsychiatry Clin Neurosci. 1990;2:268–74.PubMedGoogle Scholar
  17. Cook EH, Arora RC, Anderson GM, et al. Platelet serotonin studies in hyperserotonemic relatives of children with autistic disorder. Life Sci. 1993;52:2005–15.PubMedCrossRefGoogle Scholar
  18. Cook EH, Fletcher KE, Wainwright M, et al. Primary structure of the human platelet serotonin 5-HT2A receptor: identify with frontal cortex serotonin 5-HT2A receptor. J Neurochem. 1994;63:465–9.PubMedCrossRefGoogle Scholar
  19. Cote F, Fligny C, Bayard E, et al. Maternal serotonin is crucial for murine embryonic development. Proc Natl Acad Sci USA. 2007;104:329–34.PubMedCrossRefGoogle Scholar
  20. Coutinho AM, Oliveira G, Morgadinho T, et al. Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism. Mol Psychiatry. 2004;9:264–71.PubMedCrossRefGoogle Scholar
  21. Coutinho AM, Sousa I, Martins M, et al. Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels. Hum Genet. 2007;121:243–56.PubMedCrossRefGoogle Scholar
  22. Croonenberghs J, Delmeire L, Verkerk R, et al. Peripheral markers of serotonergic and noradrenergic function in post-pubertal, Caucasian males with autistic disorder. Neuropsychopharmacology. 2000;22:275–83.PubMedCrossRefGoogle Scholar
  23. Cuccaro ML, Wright HH, Abramson RK, et al. Whole-blood serotonin and cognitive functioning in autistic individuals and their first-degree relatives. J Neuropsychiatry Clin Neurosci. 1993;5:94–101.PubMedGoogle Scholar
  24. Deutch AY, Roth RH. Pharmacology and biochemistry of synaptic transmission: classic transmitters. In: Byrne JH, Roberts JL, editors. From molecules to networks an introduction to cellular and molecular neuroscience. Burlington: Academic; 2004. p. 245–78.CrossRefGoogle Scholar
  25. Filinger EJ, Garcia-Cotto MA, Vila S. Possible relationship between pervasive developmental disorders and platelet monoamine oxidase activity. Braz J Med Biol Res. 1987;20:161–4.PubMedGoogle Scholar
  26. Gejman PV, Owen MJ, Sanders AR. Psychiatric genetics. In: Tasman A, Kay J, Lieberman J, editors. Psychiatry. 2nd ed. West Sussex: Wiley; 2003. p. 234–53.Google Scholar
  27. Gershon MD. Roles played by 5-hydroxytryptamine in the physiology of the bowel. Aliment Pharmacol Ther. 1999;13:15–30.PubMedCrossRefGoogle Scholar
  28. Goldberg J, Anderson GM, Zwaigenbaum L, et al. Cortical serotonin type-2 receptor density in parents of children with autism spectrum disorders. J Autism Dev Disord. 2009;39:97–104.PubMedCrossRefGoogle Scholar
  29. Green AR. Neuropharmacology of 5-hydroxytryptamine. Br J Pharmacol. 2006;147:S145–52.PubMedCrossRefGoogle Scholar
  30. Hanley HG, Stahl SM, Freedman DX. Hyperserotonemia and amine metabolites in autistic and retarded children. Arch Gen Psychiatry. 1977;34:521–31.PubMedCrossRefGoogle Scholar
  31. Happé F, Ronald A, Plomin R. Time to give up on a single explanation for autism. Nat Neurosci. 2006;9:1218–20.PubMedCrossRefGoogle Scholar
  32. Hérault J, Petit E, Martineau J, et al. Serotonin and autism: biochemical and molecular biology features. Psychiatry Res. 1996;65:33–43.PubMedCrossRefGoogle Scholar
  33. Hoshino Y, Yamamoto T, Kaneko M, et al. Blood serotonin and free tryptophan concentration in autistic children. Neuropsychobiology. 1984;11:22–7.PubMedCrossRefGoogle Scholar
  34. Hranilovic D, Bujas-Petkovic Z, Vragovic R, et al. Hyperserotonemia in adults with autistic disorder. J Autism Dev Disord. 2007;37:1934–40.PubMedCrossRefGoogle Scholar
  35. Hranilovic D, Novak R, Babic M, et al. Hyperserotonemia in autism: the potential role of 5HT-related gene variants. Coll Antropol. 2008;32:75–80.PubMedGoogle Scholar
  36. Hranilovic D, Bujas-Petkovic Z, Tomicic M, et al. Hyperserotonemia in autism: activity of 5HT-associated platelet proteins. J Neural Transm. 2009;116:493–501.PubMedCrossRefGoogle Scholar
  37. Janusonis S. Serotonergic paradoxes of autism replicated in a simple mathematical model. Med Hypotheses. 2005;64:742–50.PubMedCrossRefGoogle Scholar
  38. Janusonis S, Anderson GM, Shifrovich I, et al. Ontogeny of brain and blood serotonin levels in 5-HT receptor knockout mice: potential relevance to the neurobiology of autism. J Neurochem. 2006;99:1019–31.PubMedCrossRefGoogle Scholar
  39. Katsui T, Okuda M, Usuda S, et al. Kinetics of 3 H-serotonin uptake by platelets in infantile autism and developmental language disorder (including five pairs of twins). J Autism Dev Disord. 1986;16:69–76.PubMedCrossRefGoogle Scholar
  40. Kolevzon A, Newcorn JH, Kryzak L, et al. Relationship between whole blood serotonin and repetitive behaviors in autism. Psychiatry Res. 2010;175:274–6.PubMedCrossRefGoogle Scholar
  41. Kuperman S, Beeghly JH, Burns TL, et al. Serotonin relationships of autistic probands and their first-degree relatives. J Am Acad Child Psychiatry. 1985;24:186–90.PubMedCrossRefGoogle Scholar
  42. Kuperman S, Beeghly JH, Burns TL, et al. Association of serotonin concentration to behavior and IQ in autistic children. J Autism Dev Disord. 1987;17:133–40.PubMedCrossRefGoogle Scholar
  43. Lam KSL, Aman MG, Arnold LE. Neurochemical correlates of autistic disorder: a review of the literature. Res Dev Disabil. 2006;27:254–89.PubMedCrossRefGoogle Scholar
  44. Launay JM, Ferrari P, Haimart M. Serotonin metabolism and other biochemical parameters in infantile autism: a controlled study of 22 autistic children. Neuropsychobiology. 1988;20:1–11.PubMedCrossRefGoogle Scholar
  45. Leboyer M, Philippe A, Bouvard M, et al. Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relatives. Biol Psychiatry. 1999;45:158–63.PubMedCrossRefGoogle Scholar
  46. Lesch KP, Wolozin BL, Murphy DL, et al. Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. J Neurochem. 1993;60:2319–22.PubMedCrossRefGoogle Scholar
  47. Leventhal BL, Cook EH, Morford M, et al. Relationships of whole blood serotonin and plasma norepinephrine within families. J Autism Dev Disord. 1990;20:499–511.PubMedCrossRefGoogle Scholar
  48. Makkonen I, Riikonen R, Kokki H, et al. Serotonin and dopamine transporter binding in children with autism determined by SPECT. Dev Med Child Neurol. 2008;50:593–7.PubMedCrossRefGoogle Scholar
  49. Marazziti D, Muratori F, Cesari A, et al. Increased density of the platelet serotonin transporter in autism. Pharmacopsychiatry. 2000;33:165–8.PubMedCrossRefGoogle Scholar
  50. Martineau J, Barthélémy C, Jouve J, et al. Monoamines (serotonin and catecholamines) and their derivatives in infantile autism: age-related changes and drug effects. Dev Med Child Neurol. 1992;34:593–603.PubMedCrossRefGoogle Scholar
  51. McBride PA, Anderson GM, Hertzig ME, et al. Serotonergic responsivity in male young adults with autistic disorder. Results of a pilot study. Arch Gen Psychiatry. 1989;46:213–21.PubMedCrossRefGoogle Scholar
  52. McDougle CJ, Naylor ST, Cohen DJ, et al. Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry. 1996;53:993–1000.PubMedCrossRefGoogle Scholar
  53. McDougle CJ, Stigler KA, Erickson CA, et al. Pharmacology of autism. Clin Neurosci Res. 2006;6:179–88.CrossRefGoogle Scholar
  54. Minderaa RB, Anderson GM, Volkmar FR, et al. Urinary 5-hydroxyindoleacetic acid and whole blood serotonin and tryptophan in autistic and normal subjects. Biol Psychiatry. 1987;22:933–40.PubMedCrossRefGoogle Scholar
  55. Mulder EJ, Anderson GM, Kema IP, et al. Platelet serotonin levels in pervasive developmental disorders and mental retardation: diagnostic group differences, within-group distribution, and behavioral correlates. J Am Acad Child Adolesc Psychiatry. 2004;43:491–9.PubMedCrossRefGoogle Scholar
  56. Mulder EJ, Anderson GM, Kemperman RFJ, et al. Urinary excretion of 5-hydroxyindoleacetic acid, serotonin and 6-sulphatoxymelatonin in normoserotonemic and hyperserotonemic autistic individuals. Neuropsychobiology. 2010;61:27–32.PubMedCrossRefGoogle Scholar
  57. Murphy DL, Andrews AM, Wichems CH, et al. Brain serotonin neurotransmission: an overview and update with an emphasis on serotonin subsystem heterogeneity, multiple receptors, interactions with other neurotransmitter systems, and consequent implications for understanding the actions of serotonergic drugs. J Clin Psychiatry. 1998;59:4–12.PubMedGoogle Scholar
  58. Murphy D, Daly E, Schmitz N, et al. Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger’s syndrome: an in vivo SPECT study. Am J Psychiatry. 2006;163:934–6.PubMedCrossRefGoogle Scholar
  59. Nakamura K, Sekine Y, Ouchi Y, et al. Brain serotonin and dopamine transporter bindings in adults with high-functioning autism. Arch Gen Psychiatry. 2010;67:59–68.PubMedCrossRefGoogle Scholar
  60. Owley T, Leventhal BL, Cook EH. Childhood disorders: the autism spectrum disorders. In: Tasman A, Kay J, Lieberman J, editors. Psychiatry. 2nd ed. West Sussex: Wiley; 2003. p. 757–74.Google Scholar
  61. Perry BD, Cook EH, Leventhal BL, et al. Platelet 5-HT2 serotonin receptor binding sites in autistic children and their first-degree relatives. Biol Psychiatry. 1991;30:121–30.PubMedCrossRefGoogle Scholar
  62. Persico AM, Pascucci T, Puglisi-Allegra S, et al. Serotonin transporter gene promoter variants do not explain the hyperserotoninemia in autistic children. Mol Psychiatry. 2002;7:795–800.PubMedCrossRefGoogle Scholar
  63. Piven J, Gayle J, Chase GA, et al. A family history study of neuropsychiatric disorders in the adult siblings of autistic individuals. J Am Acad Child Adolesc Psychiatry. 1990;29:177–83.PubMedCrossRefGoogle Scholar
  64. Puri RN, Colman RW. ADP-induced platelet activation. Crit Rev Biochem Mol Biol. 1997;32:437–502.PubMedCrossRefGoogle Scholar
  65. Racke K, Reimann A, Schwörer H, et al. Regulation of 5-HT release from enterochromaffin cells. Behav Brain Res. 1995;73:83–7.CrossRefGoogle Scholar
  66. Roth JA, Young JG, Cohen DJ. Platelet monoamine oxidase activity in children and adolescents. Life Sci. 1976;18:919–24.PubMedCrossRefGoogle Scholar
  67. Rotman A, Caplan R, Szekely GA. Platelet uptake of serotonin in psychotic children. Psychopharmacology. 1980;67:245–8.PubMedCrossRefGoogle Scholar
  68. Safai-Kutti S, Denfors I, Kutti J, et al. In vitro platelet function in infantile autism. Folia Haematol Int Mag Klin Morphol Blutforsch. 1988;115:897–901.PubMedGoogle Scholar
  69. Schain RJ, Freedman DX. Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J Pediatr. 1961;58:315–20.PubMedCrossRefGoogle Scholar
  70. Schwörer H, Ramadori G. Autoreceptors can modulate 5-hydroxytryptamine release from porcine and human small intestine in vitro. Naunyn Schmiedeberg’s Arch Pharmacol. 1998;357:548–52.CrossRefGoogle Scholar
  71. Stolz JF. Uptake and storage of serotonin by platelets. In: Vanhoutte PM, editor. Serotonin and the cardiovascular system. New York: Raven; 1985. p. 38–42.Google Scholar
  72. Takahashi S, Kanai H, Miyamoto Y. Monoamine oxidase activity in blood platelets from autistic children. Psychiatry Clin Neurosci. 1977;31:597–603.CrossRefGoogle Scholar
  73. Walther DJ, Bader M. A unique central tryptophan hydroxylase isoform. Biochem Pharmacol. 2003;66:1673–80.PubMedCrossRefGoogle Scholar
  74. Weiss LA, Abney M, Cook EH, et al. Sex-specific genetic architecture of whole blood serotonin levels. Am J Hum Genet. 2005;76:33–41.PubMedCrossRefGoogle Scholar
  75. Weizman A, Gonen N, Tyano S, et al. Platelet [3 H] imipramine binding in autism and schizophrenia. Psychopharmacology. 1987;91:101–3.PubMedCrossRefGoogle Scholar
  76. Whitaker-Azmitia PM. Serotonin and brain development: role in human developmental diseases. Brain Res Bull. 2001;56:479–85.PubMedCrossRefGoogle Scholar
  77. Whitaker-Azmitia PM. Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism? Int J Dev Neurosci. 2005;23:75–83.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Animal PhysiologyUniversity of Zagreb, Faculty of ScienceZagrebCroatia

Personalised recommendations