Autism-Relevant Anatomic Changes in Brain Structure in the Antigen-Driven Animal Model of Maternal Autoantibody Related Autism

Background: Numerous researchers have described the presence of maternal autoantibodies reactive to fetal brain proteins in a subset of mothers of children with autism spectrum disorder (ASD). Our lab identified 7 protein antigens for maternal autoantibody related (MAR) risk for ASD, and recently have mapped the antigenic epitope sequences recognized by these ASD-specific maternal autoantibodies. Our lab has now created an antigen-driven mouse model of MAR risk for ASD (MAR-ASD) in which autoantibodies reactive to the salient epitope sequences are generated in female dams prior to breeding, thus allowing for the continual exposure to the salient autoantibodies throughout gestation. Prenatally exposed offspring display robust deficits in social interactions and increased repetitive self-grooming behaviors as juveniles and adults during dyadic social interactions, demonstrating for the first time that these maternal autoantibodies are directly responsible for alterations in behaviors highly relevant to ASD. Furthermore, an association between maternal autoantibodies and alterations in neuronal development, including increased brain volume, has been demonstrated in previous passive transfer models as well as in the clinical population.

Objectives: The present study was designed to characterize the neuroanatomical differences in our clinically relevant antigen-driven mouse model of MAR risk of ASD using high-resolution structural MRI.

Methods: In order to generate epitope-specific autoantibodies that mimic those found in the mothers of children with ASD, C57BL/6J females randomly assigned to MAR-ASD treatment received a series of immunizations prior to breeding containing peptide epitope sequences of the four primary target proteins of MAR ASD (lactate dehydrogenase A and B, collapsin response mediator protein 1, and stress-induced phosphoprotein 1) conjugated via Multiple Antigenetic Peptide system technologies in addition to adjuvant. Control C57BL/6J females were injected with saline only. Following confirmation of autoantibody production in immunized animals by ELISA, females were then paired with male breeders to produce the experimental offspring of interest. Neuroanatomical differences in subsequent male and female offspring were assessed via high-resolution structural MRI at approximately 6 months of age (MAR-ASD = 22; Control = 23).

Results: In comparing MAR-ASD to WT adult brains, 31 of the 159 regions examined were found to be significantly different at an FDR of <5%. MAR-ASD offspring had significant increases in size of several white matter tracts, including the anterior commissure (pars anterior: +2.42%, FDR=4%; pars posterior: +3.89%, FDR=2%), cingulum (+2.52%, FDR=3%), corpus callosum (+3.19%, FDR=1%), and internal capsule (+2.67%, FDR=4%). Outside of the white matter, increases were observed in several cortical regions and in basal nuclei structures (nucleus accumbens: +2.68, FDR=2%; olfactory tubercle: +2.65%, FDR=2%; basal forebrain: +1.90%, FDR = 3%).

Conclusions: Our results suggest that numerous brain regions were significantly increased in offspring prenatally exposed to the salient maternal autoantibodies relative to controls. These findings further support the pathological role of maternal autoantibodies in ASD, with neuroanatomical alterations lasting into adulthood.