Abstract Background Rhesus monkeys ( Macaca mulatta ) exhibit pronounced individual differences in social traits as measured by the macaque Social Responsiveness Scale-Revised. The macaque Social Responsiveness Scale was previously adapted from the Social Responsiveness Scale, an instrument designed to assess social and autistic trait variation in humans. To better understand potential biological underpinnings of this behavioral variation, we evaluated the trait-like consistency of several biological measures previously implicated in autism (e.g., arginine vasopressin, oxytocin, and their receptors, as well as ERK1/2, PTEN, and AKT(1–3) from the RAS-MAPK and PI3K-AKT pathways). We also tested which biological measures predicted macaque Social Responsiveness Scale-Revised scores. Methods Cerebrospinal fluid and blood samples were collected from N = 76 male monkeys, which, as a sample, showed a continuous distribution on the macaque Social Responsiveness Scale-Revised. In a subset of these subjects ( n = 43), samples were collected thrice over a 10-month period. The following statistical tests were used: “Case 2A” intra-class correlation coefficients of consistency, principal component analysis, and general linear modeling. Results All biological measures (except AKT) showed significant test–retest reliability within individuals across time points. We next performed principal component analysis on data from monkeys with complete biological measurement sets at the first time point ( n = 57), to explore potential correlations between the reliable biological measures and their relationship to macaque Social Responsiveness Scale-Revised score; a three-component solution was found. Follow-up analyses revealed that cerebrospinal fluid arginine vasopressin concentration, but no other biological measure, robustly predicted individual differences in macaque Social Responsiveness Scale-Revised scores, such that monkeys with the lowest cerebrospinal fluid arginine vasopressin concentration exhibited the greatest social impairment. Finally, we confirmed that this result held in the larger study sample (in which cerebrospinal fluid arginine vasopressin values were available from n = 75 of the subjects). Conclusions These findings indicate that cerebrospinal fluid arginine vasopressin concentration is a stable trait-like measure and that it is linked to quantitative social trait variation in male rhesus monkeys.
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys. Using a discovery and replication design, we identified arginine vasopressin (AVP) in cerebrospinal fluid (CSF) as a key marker of group differences in monkey sociality; we replicated these findings in an independent monkey cohort. We also confirmed in an additional monkey cohort that AVP concentration in CSF is a stable trait-like measure. Next, we showed in a small pediatric cohort that CSF AVP concentrations were lower in male children with ASD compared to age-matched male children without ASD (but with other medical conditions). We demonstrated that CSF AVP concentration was sufficient to accurately distinguish ASD cases from medical controls. These data suggest that AVP and its signaling pathway warrant consideration in future research studies investigating new targets for diagnostics and drug development in ASD.
Significance Autism is a poorly understood brain disorder of childhood onset. It is characterized by social impairments and diagnosed behaviorally. Early diagnosis fosters better developmental outcomes through behavioral intervention. However, long clinic wait times to undergo behavioral evaluation contribute to delayed diagnoses and treatments. Emerging evidence indicates that low cerebrospinal fluid concentration of the “social” neuropeptide vasopressin is a marker of social impairment in children with autism. Here we report that cerebrospinal fluid vasopressin concentration is significantly lower in newborns diagnosed with autism later in childhood. These preliminary findings suggest that a biomarker of autism may be present before behavioral symptoms emerge. If replicated, this approach could be useful for assessing autism risk and facilitating early intervention in high-risk individuals.
