Project 2: Developmental neurotoxicity: Maternal anti-NMDAR antibodies and fetal development (Volpe PI) The clinical literature reports an increased incidence of learning disabilities with children of patients with systemic lupus erythematosus (SLE). We have identified a subset of anti-DNA antibodies in lupus patients that cross-reacts with the NMDA receptor (NMDAR). In a mouse model, the antibodies can cause hippocampal neuronal loss and a memory impairment, or neuronal loss in the amygdala and an emotional disturbance, depending on the agent used to breach the blood-brain barrier. We have now demonstrated that these antibodies can alter fetal brain development and cause persistent cortical deficits if present in the serum of a pregnant mouse. We will confirm these observations using serum from lupus patients administered to gestating dams. We will assess whether different monoclonal antibodies to NMDAR mediate different effects. We will determine whether different mouse strains exhibit a different vulnerability to antibody-mediated damage. These studies will form the basis for a clinical study in SLE patients and their offspring.