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Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey.

ABSTRACT: Antibodies directed against fetal brain proteins of 37 and 73?kDa molecular weight are found in approximately 12% of mothers who have children with autism spectrum disorder (ASD), but not in mothers of typically developing children. This finding has raised the possibility that these immunoglobulin G (IgG) class antibodies cross the placenta during pregnancy and impact brain development, leading to one form of ASD. We evaluated the pathogenic potential of these antibodies by using a nonhuman primate model. IgG was isolated from mothers of children with ASD (IgG-ASD) and of typically developing children (IgG-CON). The purified IgG was administered to two groups of female rhesus monkeys (IgG-ASD; n=8 and IgG-CON; n=8) during the first and second trimesters of pregnancy. Another control group of pregnant monkeys (n=8) was untreated. Brain and behavioral development of the offspring were assessed for 2 years. Behavioral differences were first detected when the macaque mothers responded to their IgG-ASD offspring with heightened protectiveness during early development. As they matured, IgG-ASD offspring consistently deviated from species-typical social norms by more frequently approaching familiar peers. The increased approach was not reciprocated and did not lead to sustained social interactions. Even more striking, IgG-ASD offspring displayed inappropriate approach behavior to unfamiliar peers, clearly deviating from normal macaque social behavior. Longitudinal magnetic resonance imaging analyses revealed that male IgG-ASD offspring had enlarged brain volume compared with controls. White matter volume increases appeared to be driving the brain differences in the IgG-ASD offspring and these differences were most pronounced in the frontal lobes.

SUBMITTER: Bauman MD

PROVIDER: S-EPMC3731783 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey.

Bauman M D MD Iosif A-M AM Ashwood P P Braunschweig D D Lee A A Schumann C M CM Van de Water J J Amaral D G DG

Translational psychiatry 20130709

Antibodies directed against fetal brain proteins of 37 and 73 kDa molecular weight are found in approximately 12% of mothers who have children with autism spectrum disorder (ASD), but not in mothers of typically developing children. This finding has raised the possibility that these immunoglobulin G (IgG) class antibodies cross the placenta during pregnancy and impact brain development, leading to one form of ASD. We evaluated the pathogenic potential of these antibodies by using a nonhuman prim ...[more]

PMID: 23838889

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Project description:Autism together with Asperger syndrome and pervasive developmental disorder not otherwise specified form a spectrum of conditions (autism spectrum disorders or ASD) that is characterized by disturbances in social behavior, impaired communication and the presence of stereotyped behaviors or circumscribed interests. Recent estimates indicate a prevalence of ASD of 1 per 150 (Kuehn, 2007). The cause(s) of most cases of ASD are unknown but there is an emerging consensus that ASD have multiple etiologies. One proposed cause of ASD is exposure of the fetal brain to maternal autoantibodies during pregnancy [Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., Vincent, A., 2003. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533-537]. To provide evidence for this hypothesis, four rhesus monkeys were exposed prenatally to human IgG collected from mothers of multiple children diagnosed with ASD. Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. Monkeys were observed in a variety of behavioral paradigms involving unique social situations. Behaviors were scored by trained observers and overall activity was monitored with actimeters. Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls. Treatment with IgG purified from mothers of typically developing children did not induce stereotypical or hyperactive behaviors. These findings support the potential for an autoimmune etiology in a subgroup of patients with neurodevelopmental disorders. This research raises the prospect of prenatal evaluation for neurodevelopmental risk factors and the potential for preventative therapeutics.

Project description:In humans, infants respond positively to slow, gentle stroking-processed by C-tactile (CT) nerve fibers-by showing reductions in stress and increases in eye contact, smiling, and positive vocalizations. More frequent maternal touch is linked to greater activity and connectivity strength in social brain regions, and increases children's attention to and learning of faces. It has been theorized that touch may prime children for social interactions and set them on a path towards healthy social cognitive development. However, less is known about the effects of touch on young infants' psychological development, especially in the newborn period, a highly sensitive period of transition with rapid growth in sensory and social processing. It remains untested whether newborns can distinguish CT-targeted touch from other types of touch, or whether there are benefits of touch for newborns' social, emotional, or cognitive development. In the present study, we experimentally investigated the acute effects of touch in newborn monkeys, a common model for human social development. Rhesus macaques (Macaca mulatta), like humans, are highly social, have complex mother-infant interactions with frequent body contact for the first weeks of life, making them an excellent model of infant sociality. Infant monkeys in the present study were reared in a neonatal nursery, enabling control over their early environment, including all caregiver interactions. One-week-old macaque infants (N?=?27) participated in three 5-minute counter-balanced caregiver interactions, all with mutual gaze: stroking head and shoulders (CT-targeted touch), stroking palms of hands and soles of feet (Non-CT touch), or no stroking (No-touch). Immediately following the interaction, infants watched social and nonsocial videos and picture arrays including faces and objects, while we tracked their visual attention with remote eye tracking. We found that, during the caregiver interactions, infants behaved differently while being touched compared to the no-touch condition, irrespective of the body part touched. Most notably, in both touch conditions, infants exhibited fewer stress-related behaviors-self-scratching, locomotion, and contact time with a comfort object-compared to when they were not touched. Following CT-targeted touch, infants were faster to orient to the picture arrays compared to the other interaction conditions, suggesting CT-targeted touch may activate or prime infants' attentional orienting system. In the No-touch condition infants attended longer to the nonsocial compared to the social video, possibly reflecting a baseline preference for nonsocial stimuli. In contrast, in both touch conditions, infants' looked equally to the social and nonsocial videos, suggesting that touch may influence the types of visual stimuli that hold infants' attention. Collectively, our results reveal that newborn macaques responded positively to touch, and touch appeared to influence some aspects of their subsequent attention, although we found limited evidence that these effects are mediated by CT fibers. These findings suggest that newborn touch may broadly support infants' psychological development, and may have early evolutionary roots, shared across primates. This study illustrates the unique insight offered by nonhuman primates for exploring early infant social touch, revealing that touch may positively affect emotional and attentional development as early as the newborn period.

Project description:BackgroundRASopathies are genetic syndromes that result from pathogenic variants in the RAS-MAPK cellular signaling pathway. These syndromes, which include neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, and Costello syndrome, are associated with a complex array of medical and behavioral health complications. Despite a heightened risk for social challenges and autism spectrum disorder (ASD), few studies have compared different aspects of social behavior across these conditions. It is also unknown whether the underlying neuropsychological characteristics that contribute to social competence and socially empathetic ("prosocial") behaviors differ in children with RASopathies as compared to children with nonsyndromic (i.e., idiopathic) ASD.MethodsIn this cross-sectional, survey-based investigation, caregivers of preschool and school-aged children with RASopathies (n = 202) or with idiopathic ASD (n = 109) provided demographic, medical, and developmental information about their child, including psychiatric comorbidities. For children who were able to communicate verbally, caregivers also completed standardized rating scales to assess social competence and empathetic behavior as well as symptoms of hyperactivity/inattention and emotional problems.ResultsAs compared to children with idiopathic ASD, children with RASopathies were rated as demonstrating more resilience in the domain of empathy relative to their overall social competence. Similarities and differences emerged in the psychological factors that predicted social behavior in these two groups. Stronger communication skills and fewer hyperactive-impulsive behaviors were associated with increased empathy and social competence for both groups. Greater emotional challenges were associated with lower social competence for children with RASopathies and stronger empathy for children with idiopathic ASD. Among children with RASopathy and a co-occurring ASD diagnosis, socially empathetic behaviors were observed more often as compared to children with idiopathic ASD.ConclusionsFindings suggest that the development of social behavior among children with RASopathies involves a distinct pattern of strengths and weaknesses as compared to a behaviorally defined disorder (idiopathic ASD). Identification of areas of resilience as well as behavioral and social challenges will support more targeted intervention.

Dataset Information

Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey.

Publications

Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey.

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