Mechanisms of anti-NMDAR Antibody Mediated Damage to the Fetal Brain

Abstract

Abstract Mothers with systemic lupus erythematosus (SLE) have an increased frequency of children with learning disorders and autism spectrum disorder (ASD) which associates with maternal anti-DNA antibodies, indicating that in utero exposure to autoantibodies may lead to neurodevelopmental alterations. A subset of anti-dsDNA antibodies present in 40% of SLE patients has been shown to cross-react with the N-methyl D-aspartate receptor (NMDAR) excitatory neuronal receptor. Immunizing mice with these antibodies (DNRAbs) causes morphological neurodevelopmental alterations and persistent behavioral and neurocognitive abnormalities in male offspring, as well as the death of a high proportion (~40%) of female fetuses due to their earlier expression of the GluN2A NMDAR subunit. The brains of the fetuses from DNRAb+ dams display increased neuronal apoptosis and thinned cortical plates, indicating alterations in neuronal migration. Male offspring of DNRAb+ dams exhibit delayed reflex acquisition, cognitive impairments in fear extinction and novel object recognition, and decreased overall cortical volume. These results parallel the substantially higher proportion of male children born to women with SLE, as well as the higher rate of developmental disorders in these children. Current studies are addressing the mechanisms of this antibody-mediated damage and whether these offspring exhibit characteristics of ASD.