The DOI matches its Crossref record; 236 of the 236 references it cites were found in a registry or an index.
The serotonin system in autism spectrum disorder: From biomarker to animal models
Open accessAbstract
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.
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In the citing paper
“ASD-associated genes were enriched for acetylcholinergic and serotonergic signaling, reflecting known biology of ASD20,21.”
From A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles (2020) · cites this paper as [21]
In the citing paper
“Additionally, the production of 5-HT can affect peripheral tryptophan availability and, thus, indirectly affect brain 5-HT levels, suggesting that peripheral alterations in 5-HT can affect the central 5-HT signaling system (390, 391).”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [390]
In the citing paper
“A number of biomarkers that could connect to microbial profiles also have been identified in ASD, including alterations in serotonin levels, IL1β, and IL6.35, 44, 45, 46, 47”
From Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder (2017) · cites this paper as [45]
In the citing paper
“Long-standing findings have indicated increased whole-blood 5-HT levels in a subset of approximately 30% of children with autism spectrum disorder,44, 45, 46, 47 as well as decreased levels of the serotonin metabolite, melatonin, in a substantial subpopulation.62”
From Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder (2017) · cites this paper as [45]
In the citing paper
“Of note, recent evidence suggests altered 5-HT and kynurenine metabolism in ASD (Boccuto et al., 2013; Lim et al., 2015; Muller et al., 2016).”
From Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism (2017) · cites this paper as Muller et al., 2016
In the citing paper
“Although most serotonin, or 5′-HT, is produced in the GI tract and can also be metabolized directly by the gut microbiota, it modulates neurodevelopment and might be important in social function and repetitive behavior [188].”
From Autism, Gastrointestinal Symptoms and Modulation of Gut Microbiota by Nutritional Interventions (2019) · cites this paper as [188]
In the citing paper
“In patients with ASD, altered function and metabolism of neurotransmitters, such as 5′-HT and catecholamines, and dysfunction of the serotonergic system have been reported to contribute to symptomatology [188,192,193,194,195,196].”
From Autism, Gastrointestinal Symptoms and Modulation of Gut Microbiota by Nutritional Interventions (2019) · cites this paper as [188]
In the citing paper
“studies revealed that approximately 30% of individuals with ASD exhibited an increase in whole-blood 5-HT levels, termed hyperserotonemia [35, 36].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [36]
In the citing paper
“They identified five variants that were overexpressed in the individuals with ASD; each variant was a gain-of-function mutation that conferred a hyperactivity to SERT [36, 52].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [36]
In the citing paper
“the clinical correlates between hyperserotonemia and ASD-associated behaviors (e.g., stereotypy and self-injury) have been inconsistent [36, 45–47].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [36]
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Metadata
- Authors
- Muller, C. L., Anacker, A. M. J., & Veenstra-VanderWeele, J.
- Affiliations
- Vanderbilt University (US)
- Columbia University (US)
- NewYork–Presbyterian Hospital (US)
- Corresponding author
- Veenstra-VanderWeele, J.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 321
- Pages
- 24-41
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC4824539
- OpenAlex
- W2119744351
- Cited by
- 531
- References
- 236
- Citations by year
- 2026: 54 · 2025: 44 · 2024: 55 · 2023: 60 · 2022: 50 · 2021: 63 · 2020: 59 · 2019: 48 · 2018: 45 · 2017: 33 · 2016: 18
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (MH094604)
- New York State Psychiatric Institute
- Mortimer D. Sackler Chair Fund
- Columbia University
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Keywords
- autism spectrum disorder, serotonergic system, hyperserotonemia, whole blood serotonin, serotonin transporter gene, knock-in mice, heritability, recurrence risk, serotonin receptors, social behavior, oxytocin, cognitive flexibility, sensory development, ASD pathophysiology
- MeSH terms
- Autism Spectrum Disorder, Animals, Brain, Disease Models, Animal, Female, Humans, Genetic Linkage, Male, Mice, Mutant Strains, Serotonin, Sex Factors, Biomarkers, Serotonin Plasma Membrane Transport Proteins, Genetic Association Studies
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