An initial attempt to determine whether antibodies derived from mothers of autistic children could have pathological effects on offspring was carried out in the mouse model. Plasma from one mother of multiple children with autism was injected into pregnant mice and the offspring demonstrated impaired exploratory behavior and motor coordination (Dalton et al., 2003
). Another study purified IgG from several mothers of children with autism and injected the cocktail into pregnant mice. Abnormal behavior was again observed, which included increased anxiety and motor activity and abnormal startle reflexes and sociability (Singer et al., 2009
). A more recent study determined the effects of gestational exposure to a single, intravenous dose of purified brain-reactive IgG antibodies from individual mothers of children with autism (MAU). The outcome revealed alterations in early growth trajectories, significantly impaired motor and sensory development, and increased anxiety in the offspring of treated dams. This study demonstrated, for the first time, that a single, low dose gestational exposure of IgG derived from individual MAU with specific reactivity to the 37 and 73 kDa fetal brain proteins had significant effects on the physical and social development of the gestationally-exposed offspring (Braunschweig et al., 2012
). Further development of the murine model, including modifications to dosage, use of the specific antigen proteins, age at evaluation of social behavior and mouse strain, will allow for greater precision in determining the critical developmental windows that are perturbed in maternal antibody associated autism.
When one considers which animal model to employ to examine hypotheses of causality, it is important to consider which behaviors and which brain systems may be most involved in the disease process. Autism is a disorder of higher cognitive function that likely involves regions such as the frontal lobe that is not well developed in the rodent. Rhesus macaques (Macaca mulatta) demonstrate many similarities with human physiology, anatomy, and behavior. For example, despite the fact that a rhesus monkey brain is ten times smaller than a human brain, there are no regions of the human brain that have not been found in the rhesus monkey brain; the same cannot be said for the mouse brain.
The maternal antibody hypothesis of autism has also been investigated using a nonhuman primate model. The first study (Martin et al 2008
) demonstrated the effects of exposing pregnant rhesus monkeys to IgG class antibodies from human mothers of multiple children with ASD obtained from the Autism Genetic Resource Exchange (AGRE). Rhesus monkeys prenatally exposed to this pool of maternal antibodies produced more whole body motor stereotypies and hyperactivity compared to both untreated control monkeys and monkeys prenatally exposed to IgG class antibodies from mothers of typically developing children (Martin et al., 2008
). Perhaps even more intriguing, a second group of animals has now been treated with IgG derived from mothers who demonstrate the specific 37kDa and 73kDa associated with children who specifically have a diagnosis of ASD. Not only do these animals demonstrate inappropriate social behavior, but also magnetic resonance imaging analysis has demonstrated that they demonstrate a pattern of abnormal brain development that is characteristic of autistic children who have been exposed to the 37/73kDa antibodies in utero (Nordahl et al. IMFAR presentation; Bauman et al, submitted
). This monkey model of antibody-induced behavioral and brain development impairment may prove to be a valuable adjunct to epidemiological and clinical data that abnormal antibody exposure during gestation may produce one form of autism. Equally important, this model opens up exciting new areas of exploration concerning the underlying pathology that leads to abnormal brain growth in autism. And, if this model continues to be replicated, it will provide a substrate for evaluating potential interventions and preventative measures.