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. 2013 Jul 9;3(7):e278.
doi: 10.1038/tp.2013.47.

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

M D Bauman  1 , A-M Iosif, P Ashwood, D Braunschweig, A Lee, C M Schumann, J Van de Water, D G Amaral
Affiliations

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

M D Bauman et al. Transl Psychiatry. .

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.

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Figures

Figure 1
Figure 1
Immunoglobulin G (IgG)-autism spectrum disorder (ASD) offspring receive approach, contact and proximity more frequently from their mothers during daily rearing group socialization. Bars represent the mean frequency ±s.e.m. per 5-min observation period across all observations from 0 to 6 months of age. *P<0.05.
Figure 2
Figure 2
Immunoglobulin G (IgG)-autism spectrum disorder (ASD) offspring consistently deviate from species-typical social interactions by more frequently approaching familiar and unfamiliar peers. Bars represent the mean frequency ±s.e.m. per 5-min observation period across all observations. (a) Approach to familiar peers during daily post-weaning group observations 6–12 months of age. (b) Approach to juvenile familiar peers during daily juvenile group observations 12–18 months of age. (c) Approach to unfamiliar peers during unconstrained novel dyads at 12 months of age. (d) Approach to unfamiliar peers housed in a stimulus cage during the three-chambered social approach assay at 16 months of age. *P<0.05.
Figure 3
Figure 3
Unlike control juveniles, immunoglobulin G (IgG)-autism spectrum disorder (ASD) juveniles fail to show a species-typical correlation between the total number of affiliative behaviors initiated and the total number of affiliative behaviors received from peers. Total affiliative behaviors represent a composite score of all positive vocalizations (coo, grunt, girney), facial expressions (lipsmack, play, threat) and movements (approach, follow, play, groom, mount, approach, contact, proximity) not associated with negative behaviors (aggressive contact, and so on).
Figure 4
Figure 4
Immunoglobulin G (IgG)-autism spectrum disorder (ASD) males demonstrate a higher rate of brain growth resulting in significant differences in total brain volume emerging between 3 and 6 months of age.
Figure 5
Figure 5
Parcellation of five cerebral lobes: frontal (red), cingulate (purple), temporal (green), parietal (yellow), occipital (blue) on the lateral and medial surface on an magnetic resonance imaging (MRI) three-dimensional reconstruction of the macaque brain. Coronal images from rostral (left) to caudal (right) indicating segmentation of lobes into gray (dark exterior color band) and white (light interior color) matter within each lobe parcellation.
Figure 6
Figure 6
At two years of age, IgG-ASD male offspring demonstrate (a) trend towards increased total gray matter and (b) significantly more white matter than controls. *P<0.05.
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