The serotonin-N-acetylserotonin–melatonin pathway as a biomarker for autism spectrum disorders

Pagan, Cécile; Delorme, Richard; Crinon, Jacques; Goubran‐Botros, Hany; Amsellem, Frédérique; Drouot, Xavier; Boudebesse, C.; Dudal, K. Le; Ngo-Nguyen, N; Laouamri, H.; Gillberg, Christopher; Leboyer, Marion; Bourgeron, Thomas; Launay, J. M.

doi:10.1038/tp.2014.120

Cited by 129 publications

(156 citation statements)

References 69 publications

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“…4, path B, as “melatonin” only). This confirms previous assessments performed in plasma or urine [10, 49–52], while lending further support to blunted melatonin synthesis possibly due to reduced ASMT enzyme activity in ASD [53, 54]. Melatonin is synthesized and released by the pineal gland into the systemic circulation and readily passes the blood-brain barrier [55].…”

Section: Discussionsupporting

confidence: 85%

Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism

et al. 2016

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BackgroundAutism spectrum disorder (ASD) is still diagnosed through behavioral observation, due to a lack of laboratory biomarkers, which could greatly aid clinicians in providing earlier and more reliable diagnoses. Metabolomics on human biofluids provides a sensitive tool to identify metabolite profiles potentially usable as biomarkers for ASD. Initial metabolomic studies, analyzing urines and plasma of ASD and control individuals, suggested that autistic patients may share some metabolic abnormalities, despite several inconsistencies stemming from differences in technology, ethnicity, age range, and definition of “control” status.MethodsASD-specific urinary metabolomic patterns were explored at an early age in 30 ASD children and 30 matched controls (age range 2–7, M:F = 22:8) using hydrophilic interaction chromatography (HILIC)-UHPLC and mass spectrometry, a highly sensitive, accurate, and unbiased approach. Metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathway.ResultsUrinary metabolites displaying the largest differences between young ASD and control children belonged to the tryptophan and purine metabolic pathways. Also, vitamin B6, riboflavin, phenylalanine-tyrosine-tryptophan biosynthesis, pantothenate and CoA, and pyrimidine metabolism differed significantly. ASD children preferentially transform tryptophan into xanthurenic acid and quinolinic acid (two catabolites of the kynurenine pathway), at the expense of kynurenic acid and especially of melatonin. Also, the gut microbiome contributes to altered tryptophan metabolism, yielding increased levels of indolyl 3-acetic acid and indolyl lactate.ConclusionsThe metabolic pathways most distinctive of young Italian autistic children largely overlap with those found in rodent models of ASD following maternal immune activation or genetic manipulations. These results are consistent with the proposal of a purine-driven cell danger response, accompanied by overproduction of epileptogenic and excitotoxic quinolinic acid, large reductions in melatonin synthesis, and gut dysbiosis. These metabolic abnormalities could underlie several comorbidities frequently associated to ASD, such as seizures, sleep disorders, and gastrointestinal symptoms, and could contribute to autism severity. Their diagnostic sensitivity, disease-specificity, and interethnic variability will merit further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0109-5) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 85%

Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism

et al. 2016

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“…Several studies [150][151][152] , which have not all been replicated 153 , have reported an increase in BDNF levels in the blood of patients with ASD. In addition, high plasma levels of serotonin and N-acetylserotonin, as well as low plasma levels of melatonin, are more frequently observed in individuals with ASD than in controls 154,155 . Given that N-acetylserotonin is a potent agonist of the BDNF receptor tropomyosin-related kinase B (TRKB; also known as NTRK2) 156 , an excess of this molecule could increase TRKB-induced phosphoinositide 3-kinase signalling, thus leading to higher protein synthesis, similarly to the effect of mutations affecting regulators of the mTOR pathway.…”

Section: Synaptic Homeostasis and Asdsmentioning

confidence: 99%

From the genetic architecture to synaptic plasticity in autism spectrum disorder

2015

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Genetics studies of autism spectrum disorder (ASD) have identified several risk genes that are key regulators of synaptic plasticity. Indeed, many of the risk genes that have been linked to these disorders encode synaptic scaffolding proteins, receptors, cell adhesion molecules or proteins that are involved in chromatin remodelling, transcription, protein synthesis or degradation, or actin cytoskeleton dynamics. Changes in any of these proteins can increase or decrease synaptic strength or number and, ultimately, neuronal connectivity in the brain. In addition, when deleterious mutations occur, inefficient genetic buffering and impaired synaptic homeostasis may increase an individual's risk for ASD.

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“…The primary metabolite of serotonin, 5-HIAA, is also increased in the urine in a few ASD studies, with little evidence that there is altered metabolism of 5-HT (Hanley et al, 1977b, Minderaa et al, 1994, Mulder et al, 2010). Interestingly, one study reported that N-acetylserotonin (NAS), which is a precursor in melatonin synthesis, is also increased in ASD, but neither NAS nor melatonin show a correlation with 5-HT levels despite a robust negative correlation between NAS and melatonin levels (Pagan et al, 2014). …”

Section: Potential Mechanisms Of Hyperserotonemiamentioning

confidence: 99%

The serotonin system in autism spectrum disorder: From biomarker to animal models

2016

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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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The serotonin-N-acetylserotonin–melatonin pathway as a biomarker for autism spectrum disorders

Cited by 129 publications

References 69 publications

Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism

Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism

From the genetic architecture to synaptic plasticity in autism spectrum disorder

The serotonin system in autism spectrum disorder: From biomarker to animal models

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