Gestational autoantibody exposure impacts early brain development in a rat model of MAR autism

Abstract

Maternal autoantibody-related autism (MARA) is a subtype of autism characterized by the maternal production of specific patterns of autoantibodies during pregnancy, which significantly increases the likelihood of an autism diagnosis in their children. Multiple patterns of MARA autoantibodies (MARA-ABS) have been identified, and differences in the severity of the autism phenotype associated with each autoantibody pattern have been described. In this study, we utilized preclinical rat models to further elucidate the differential effects of MARA-AB exposure based on the known clinical patterns, including the originally reported pattern of lactate dehydrogenase A and B (LDHA/B) + collapsin response mediator protein 1 (CRMP1) + stress-induced phosphoprotein 1 (STIP1), as well as the more recently described patterns of CRMP1+CRMP2, CRMP1 + guanine deaminase (GDA), and STIP1+ neuron-specific enolase (NSE). We induced endogenous MARA-AB production in rat dams before pregnancy to expose offspring to the ABs throughout gestation. We found that in postnatal day 2 offspring exposed to MARA-ABS, the levels of brain and serum cytokines/chemokines/growth factors were altered based on the pattern of MARA-AB exposure. Further, bulk transcriptomic profiles of coronal sections containing hippocampal formation and the adjacent cortical and subcortical structures suggested changes in cellular proliferation and differentiation following MARA exposure. These combined observations demonstrate that gestational exposure to MARA-ABS alters early gene expression and immune signaling molecules, both of which may contribute to the altered neurodevelopment and behaviors associated with MARA.