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.

Keywords: genetic; monoamine; multisensory; neurodevelopment; platelet; reuptake.

Figure 1. Overview of the Serotonin System

This cartoon depicts the serotonin synthesis, release, reuptake, and degradation, as well as the canonical roles of a subset of serotonin receptors. TPH = tryptophan hydroxylase. AADC = aromatic acid decarboxylase. VMAT = vesicular monoamine transporter. SERT = serotonin transporter. MAO = monoamine oxidase. 5HT1-7 = serotonin receptor subgroups (oval shape) and individual receptors (goblet shape). Figure created using Ingenuity Pathway Analysis (Qiagen, Valencia, CA).

Figure 2. Venn Diagram of the Serotonin System and Autism Spectrum Disorder

Key roles or research findings within the serotonin system are shown in the purple circle on the left. Research or clinical findings in autism spectrum disorder are depicted in the teal circle on the right. The overlapping blue region demonstrates findings directly related to serotonin in ASD. Some findings in ASD, such as constipation, overlap with known roles of the serotonin system, such as gut motility – even though they have not been directly connected – and these are shown in black type in parallel positions within the corresponding circles. Other findings, such as somatic overgrowth or regulation of vasoconstriction, so no such overlap, and these are shown in gray type.