Antigen-Driven Rat Model of Maternal Autoantibody Related Autism

Background: Maternal autoantibodies reactive to proteins in the developing fetal brain have been previously described in a subset of mothers of children with autism spectrum disorder (ASD), but not in mothers of typically developing children.

Objectives: We recently developed an active immunization rat model of maternal autoantibody related (MAR) ASD that mimics those found in the mothers of children with ASD to directly assess the pathologic significance of prenatal exposure to epitope-specific autoantibodies, and to evaluate the impact of maternal autoantibody exposure on complex, reciprocal play behavior as well as longitudinal MRI and MRS spectroscopy of the brain.

Methods: We generated epitope-specific autoantibodies in female rats through a series of immunizations containing the immunodominant peptide epitopes of the four primary target proteins of MAR-ASD (LDH A and B, CRMP1, and STIP1). Control females were injected with saline/adjuvant only. Autoantibody-positive females were bred, and male and female offspring were tested for autism-relevant behaviors and developmental milestones from early postnatal through adulthood. We also evaluated adult MAR (N=8) and control offspring (N=8) evaluated with a pro-social motivation assay.

Results: Offspring prenatally exposed to MAR-ASD antibodies emitted fewer ultrasonic vocalizations as pups at postnatal day 12 (p=<0.05), spent less overall time engaged in social interaction as juvenile and young adults (p=<0.05), and specifically spent less time in reciprocal play behavior as juveniles (p=<0.05) and engaged in more self-grooming behavior as adults (p=<0.05). MAR offspring demonstrated differences in time-to-release of their dyad partner from a confinement chamber compared to controls.

Conclusions: The developmental trajectory of social impairments and repetitive behaviors observed in the MAR rats parallels features of human autism and lends support to prenatal autoantibody exposure as a risk factor for ASD. Further, the MAR rats appear to be less interested in the release of their dyad partners based on the increase in time to release from the confinement chamber over time.