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Examining Autism Spectrum Disorders by Biomarkers: Example From the Oxytocin and Serotonin Systems

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Objective

Autism spectrum disorder (ASD) is a heritable but highly heterogeneous neuropsychiatric syndrome, which poses challenges for research relying solely on behavioral symptoms or diagnosis. Examining biomarkers may give us ways to identify individuals who demonstrate specific developmental trajectories and etiological factors related to ASD. Plasma oxytocin (OT) and whole-blood serotonin (5-HT) levels are consistently altered in some individuals with ASD. Reciprocal relationships have been described between brain oxytocin and serotonin systems during development. We therefore investigated the relationship between these peripheral biomarkers as well as their relationships with age.

Method

In our first study, we analyzed correlations between these two biomarkers in 31 children and adolescents who were diagnosed with autism and were not on medications. In our second study, we explored whether whole-blood 5-HT levels are altered in mice lacking the oxytocin receptor gene Oxtr.

Results

In humans, OT and 5-HT were negatively correlated with each other (p < .05) and this relationship was most prominent in children less than 11 years old. Paralleling human findings, mice lacking Oxtr showed increased whole-blood 5-HT levels (p = .05), with this effect driven exclusively by mice less than 4 months old (p < .01).

Conclusions

Identifying relationships between identified ASD biomarkers may be a useful approach to connect otherwise disparate findings that span multiple systems in this heterogeneous disorder. Using neurochemical biomarkers to perform parallel studies in animal and human populations within a developmental context is a plausible approach to probe the root causes of ASD and to identify potential interventions.

Section snippets

Human Participants

All participants were enrolled at the University of Illinois at Chicago Autism Center of Excellence, and were recruited under a protocol studying rigid-compulsive features in ASD. They were assessed with the Autism Diagnostic Interview—Revised (ADI-R),90 the Autism Diagnostic Observation Schedule (ADOS),91 and clinical evaluation. Participants were included in this study if they were classified as having strictly defined autism rather than autism spectrum disorder, because they met the

Results

We initially examined whether human OT plasma levels and WB5-HT were normally distributed and whether they differed by sex, reported ancestral background, and age (Table S1, available online). Although WB5-HT approached a normal distribution, OT was positively skewed (skewness = 2.7, kurtosis = 10.3) and required log transformation in all further analyses.

There were no significant differences in log(OT) and WB5-HT across sex (all p values >0.30) or reported ancestral background (all p values

Discussion

Both the human and murine data are consistent with a relationship between peripheral OT and 5-HT biomarkers. In humans, we observed a negative correlation between whole-blood serotonin levels and peripheral OT levels. In mice, we observed that mice lacking the Oxtr gene had higher concentrations of whole-blood serotonin. Both in humans and in mice, the relationships were strongest in younger individuals.

The negative correlation between OT and 5-HT levels in the human data can be interpreted in

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  • Cited by (0)

    This work was supported in part by a Vanderbilt Luton Society Research Award (J.V., E.H.), a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award (E.H.), a National Institutes of Health (NIH) grant K08MH081066 (J.V.), the National Institute of Child Health and Human Development (NICHD) grant P30HD15052 to the Vanderbilt Kennedy Center for Research on Human Development (E.H., J.V.), NIH Autism Center of Excellence grants P50 HD055751 (E.H.C.), and K23MH082121 (S.J.).

    Disclosure: Dr. Veenstra-VanderWeele has received funding from Seaside Therapeutics, Novartis, and Roche Pharmaceuticals, and has served as a consultant for Novartis. Dr. Cook has served as a consultant for and has received funding from Seaside Therapeutics. Drs. Hammock, Yan, Morris, Anderson, Carter, and Jacob, and Mr. Kerr report no biomedical financial interests or potential conflicts of interest.

    Supplemental material cited in this article is available online.

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