title: The serotonin system in autism spectrum disorder: From biomarker to animal models.
abstract: Elevated whole blood serotonin, or hyperserotonemia, was the first biomarker identified in autism spectrum disorder (ASD) and is present in more than 25% of affected children. The serotonin system is a logical candidate for involvement in ASD due to its pleiotropic role across multiple brain systems both dynamically and across development. Tantalizing clues connect this peripheral biomarker with changes in brain and behavior in ASD, but the contribution of the serotonin system to ASD pathophysiology remains incompletely understood. Studies of whole blood serotonin levels in ASD and in a large founder population indicate greater heritability than for the disorder itself and suggest an association with recurrence risk. Emerging data from both neuroimaging and postmortem samples also indicate changes in the brain serotonin system in ASD. Genetic linkage and association studies of both whole blood serotonin levels and of ASD risk point to the chromosomal region containing the serotonin transporter (SERT) gene in males but not in females. In ASD families with evidence of linkage to this region, multiple rare SERT amino acid variants lead to a convergent increase in serotonin uptake in cell models. A knock-in mouse model of one of these variants, SERT Gly56Ala, recapitulates the hyperserotonemia biomarker and shows increased brain serotonin clearance, increased serotonin receptor sensitivity, and altered social, communication, and repetitive behaviors. Data from other rodent models also suggest an important role for the serotonin system in social behavior, in cognitive flexibility, and in sensory development. Recent work indicates that reciprocal interactions between serotonin and other systems, such as oxytocin, may be particularly important for social behavior. Collectively, these data point to the serotonin system as a prime candidate for treatment development in a subgroup of children defined by a robust, heritable biomarker.
authors.affiliation: Vanderbilt Brain Institute, Vanderbilt University, 465 21st Avenue South, Nashville, TN 37232, USA. Electronic address: christopher.l.muller@vanderbilt.edu.
authors.forename: C L
authors.initials: CL
authors.lastname: Muller
authors.affiliation: Department of Psychiatry, Columbia University, 1051 Riverside Drive, Mail Unit 78, New York, NY 10032, USA. Electronic address: aanacke@nyspi.columbia.edu.
authors.forename: A M J
authors.initials: AMJ
authors.lastname: Anacker
authors.affiliation: Sackler Institute for Developmental Psychobiology, Department of Psychiatry, Columbia University; Center for Autism and the Developing Brain, New York Presbyterian Hospital; New York State Psychiatric Institute, 1051 Riverside Drive, Mail Unit 78, New York, NY 10032, USA. Electronic address: veenstr@nyspi.columbia.edu.
authors.forename: J
authors.initials: J
authors.lastname: Veenstra-VanderWeele
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008817:Mice, Mutant Strains; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors
chemical_list: D015415:Biomarkers; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin
keywords: genetic; monoamine; multisensory; neurodevelopment; platelet; reuptake