A monoclonal antibody from a mother of a child with autism resulted in cortical and behavioral alterations in male but not in female mice

Abstract

Maternal brain-reactive antibodies have been associated with increased risk for neuropsychiatric disorders including autism spectrum disorders (ASD) in the offspring. Maternal brain-reactive antibodies can affect the fetal brain before it develops a competent blood brain barrier that prevents exposure to antibody. Approximately 10% of women with a child with ASD have brain-reactive antibodies, while these antibodies present only in 2% of women of child bearing age. Previous studies have used polyclonal serum to study maternal antigenic specificities, and the postnatal effects. We opted to generate monoclonal brain-reactive antibodies to study the antigenic specificities of the brain-reactive antibodies and to determine which contribute to ASD pathogenesis. Here, we show in a mouse model that exposure in-utero to a monoclonal anti-brain reactive antibody isolated from a mother of an ASD child induces neurodevelopmental effects in the offspring that can be observed already during the embryonic stage. We identified brain-reactive B cells in blood of women with brain-reactive immunoglobulin G (IgG) and a child with ASD and generated monoclonal (Mab) brain-reactive antibodies by single cell cloning and expression. Protein array analysis demonstrated that one of the Mabs, C6 targets a subunit of potassium channel (KCNAB2). When this Mab was administrated to pregnant mice at E13 only male but not female mice showed thinning of the cortical plate and fewer mitotic cells (PH3 staining) at E15 compared to control embryos of mice injected with a non-brain reactive Mab. When pregnancies were allowed to reach full term, male but not female mice born to a mother injected with C6 displayed greater anxiety in open field test, impaired motor balance in the rotarod test and spent less time near a fellow mouse in the social preference test. Synaptic pruning defects are currently being evaluated.