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 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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
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.
Anderson GM. Monoamines in autism: an update of neurochemical research on a pervasive developmental disorder. Med Biol. 1987;65:67–74.
Anderson GM, Minderaa RB, van Benthem PP, et al. Platelet imipramine binding in autistic subjects. Psychiatry Res. 1984;11:133–41.
Anderson GM, Horne WC, Chatterjee D, et al. The hyperserotonemia of autism. Ann N Y Acad Sci. 1990;600:331.
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.
Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355–66.
Betancur C, Corbex M, Spielewoy C, et al. Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder. Mol Psychiatry. 2002;7:67–71.
Billett EE. Monoamine oxidase (MAO) in human peripheral tissues. Neurotoxicology. 2004;25:139–48.
Boullin DJ, Bhagavan HN, Coleman M, et al. Platelet monoamine oxidase in children with infantile autism. Med Biol. 1975;53:210–3.
Brzezinski A. Melatonin in humans. N Engl J Med. 1997;336:186–95.
Bursztejn C, Ferrari P, Dreux C, et al. Metabolism of serotonin in autism in children. Encéphale. 1988;14:413–9.
Campbell M, Friedman E, DeVito E. Blood serotonin in psychotic and brain damaged children. J Autism Child Schizophr. 1974;4:33–41.
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.
Chugani DC. Serotonin in autism and pediatric epilepsies. Ment Retard Dev Disabil Res. 2004;10:112–6.
Cohen DJ, Young JG. Platelet monoamine oxidase in early childhood autism. Arch Gen Psychiatry. 1977;34:534–7.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Gershon MD. Roles played by 5-hydroxytryptamine in the physiology of the bowel. Aliment Pharmacol Ther. 1999;13:15–30.
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.
Green AR. Neuropharmacology of 5-hydroxytryptamine. Br J Pharmacol. 2006;147:S145–52.
Hanley HG, Stahl SM, Freedman DX. Hyperserotonemia and amine metabolites in autistic and retarded children. Arch Gen Psychiatry. 1977;34:521–31.
Happé F, Ronald A, Plomin R. Time to give up on a single explanation for autism. Nat Neurosci. 2006;9:1218–20.
Hérault J, Petit E, Martineau J, et al. Serotonin and autism: biochemical and molecular biology features. Psychiatry Res. 1996;65:33–43.
Hoshino Y, Yamamoto T, Kaneko M, et al. Blood serotonin and free tryptophan concentration in autistic children. Neuropsychobiology. 1984;11:22–7.
Hranilovic D, Bujas-Petkovic Z, Vragovic R, et al. Hyperserotonemia in adults with autistic disorder. J Autism Dev Disord. 2007;37:1934–40.
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.
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.
Janusonis S. Serotonergic paradoxes of autism replicated in a simple mathematical model. Med Hypotheses. 2005;64:742–50.
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.
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.
Kolevzon A, Newcorn JH, Kryzak L, et al. Relationship between whole blood serotonin and repetitive behaviors in autism. Psychiatry Res. 2010;175:274–6.
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.
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.
Lam KSL, Aman MG, Arnold LE. Neurochemical correlates of autistic disorder: a review of the literature. Res Dev Disabil. 2006;27:254–89.
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.
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.
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.
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.
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.
Marazziti D, Muratori F, Cesari A, et al. Increased density of the platelet serotonin transporter in autism. Pharmacopsychiatry. 2000;33:165–8.
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.
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.
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.
McDougle CJ, Stigler KA, Erickson CA, et al. Pharmacology of autism. Clin Neurosci Res. 2006;6:179–88.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Puri RN, Colman RW. ADP-induced platelet activation. Crit Rev Biochem Mol Biol. 1997;32:437–502.
Racke K, Reimann A, Schwörer H, et al. Regulation of 5-HT release from enterochromaffin cells. Behav Brain Res. 1995;73:83–7.
Roth JA, Young JG, Cohen DJ. Platelet monoamine oxidase activity in children and adolescents. Life Sci. 1976;18:919–24.
Rotman A, Caplan R, Szekely GA. Platelet uptake of serotonin in psychotic children. Psychopharmacology. 1980;67:245–8.
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.
Schain RJ, Freedman DX. Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J Pediatr. 1961;58:315–20.
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.
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.
Takahashi S, Kanai H, Miyamoto Y. Monoamine oxidase activity in blood platelets from autistic children. Psychiatry Clin Neurosci. 1977;31:597–603.
Walther DJ, Bader M. A unique central tryptophan hydroxylase isoform. Biochem Pharmacol. 2003;66:1673–80.
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.
Weizman A, Gonen N, Tyano S, et al. Platelet [3 H] imipramine binding in autism and schizophrenia. Psychopharmacology. 1987;91:101–3.
Whitaker-Azmitia PM. Serotonin and brain development: role in human developmental diseases. Brain Res Bull. 2001;56:479–85.
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.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this entry
Cite this entry
Hranilovic, D., Blazevic, S. (2014). Hyperserotonemia in Autism: 5HT-Regulating Proteins. In: Patel, V., Preedy, V., Martin, C. (eds) Comprehensive Guide to Autism. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4788-7_34
Download citation
DOI: https://doi.org/10.1007/978-1-4614-4788-7_34
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-4787-0
Online ISBN: 978-1-4614-4788-7
eBook Packages: Behavioral Science