Abstract
Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F 1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F 1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.
Highlights
Autism spectrum disorder (ASD) is characterized by core deficits in social behavior and communication, and affects an estimated 1 in 68 U.S children [1]
In line with our recent study of neonatal humans [24], we found that blood arginine vasopressin (AVP) concentrations significantly and positively predicted cerebrospinal fluid (CSF) AVP concentrations (F1,26 = 7.17, r = 0.46, p = 0.0127; Fig 1) in this independent, older cohort
The relationship between blood AVP concentrations and Theory of Mind score did, differ between children with and without ASD (F1,144 = 5.83, p = 0.017; Fig 2). This relationship did not differ between children with autistic disorder and PDD-NOS versus sibling and control subgroups (F2,144 = 0.07, p = 0.933), confirming that these subgroups could be combined into the larger ASD and non-ASD groups used in all subsequent analyses
Summary
Autism spectrum disorder (ASD) is characterized by core deficits in social behavior and communication, and affects an estimated 1 in 68 U.S children [1]. Central administration of selective AVPv1a receptor (AVPRv1a) antagonists, in the presence of normal brain OXT signaling, impairs social functioning in rodents [15, 16] These pharmacological effects are especially evident in males, and given ASD’s male-biased prevalence, brain AVP peptide signaling deficits may be relevant to understanding the risk for ASD. Blood AVP concentrations likewise were not examined in ASD discordant siblings, despite the possibility that AVP concentrations could be related to the “broad autism phenotype”, in which relatives of individuals with ASD show subclinical impairments in social and biological functioning [20,21,22] It remains unknown whether blood AVP concentrations are related to CSF AVP concentrations, or whether AVP concentrations are related to ASD diagnosis or predict social functioning in people with ASD, their unaffected relatives, and/or neurotypical controls. ASD discordant siblings, and neurotypical controls; and 3) predict social functioning performance in a large, well-characterized child cohort
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