In utero exposure to endogenous maternal polyclonal anti-Caspr2 antibody leads to an autism-like phenotype in male mice

Abstract

Abstract Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with a complex etiology. A strong sex bias has been observed in ASD with boys being four times more likely to be diagnosed than girls. The maternal immune system has been repeatedly implicated in the etiology of ASD. Maternal infection with fever during pregnancy has been linked to ASD. Increased levels of maternal cytokines and chemokines during gestation, including interleukin 6, have been associated with ASD in children with intellectual disabilities. Studies, including our own, have consistently supported the hypothesis that maternal brain-reactive antibodies can predispose to ASD by affecting the developing brain during a critical period. We have previously demonstrated that antibodies targeting the neuronal protein Caspr2 are present at high frequency in mothers with brain-reactive serology and a ASD child. Furthermore, male mice but not female mice exposed in utero to a monoclonal anti-Caspr2 antibody cloned from a mother of a child with ASD, develop an ASD -like phenotype. In the present study we use a new model in which female mice are immunized with the extracellular portion of Caspr2, and therefore harbor anti-Caspr2 antibodies throughout gestation to mimic the human condition. Male mice born to dams harboring polyclonal anti-Caspr2 antibodies exhibit abnormal cortical development, decreased dendritic complexity of excitatory neurons and reduced numbers of inhibitory neurons in the hippocampus, as well as repetitive behaviors and impairments in social interactions as adults. These studies will increase our understanding of the triggers of neurodevelopmental impairment and possibly suggest novel approaches to protecting the fetal brain.