Maternal Antibodies and Cognitive Dysfunction in the Offspring

A subset of anti-DNA antibodies present in the serum of patients with systemic lupus cross-reacts with the NR2A and NR2B subunits of the NMDA receptor (NMDAR).  The presence of these antibodies in cerebrospinal fluid of patients correlates with central nervous system manifestations of disease.  Furthermore, these antibodies can be eluted from brain tissue of lupus patients.
     Studies in cultured cells and in mice show that the antibodies function as receptor co-agonists synergizing with glutamate to activate NMDARs.  As co-agonists, they can mediate excitotoxic neuronal death.  In vivo models demonstrate that these antibodies can alter either memory function or behavior if they can penetrate the blood-brain barrier and access the hippocampus or amygdala, respectively.
     Because it has been reported that the children of mothers with lupus have a 2-5 fold increased incidence of learning disabilities, we asked whether anti-DNA, anti-NMDAR, cross-reactive antibodies might alter fetal brain development when maternal antibodies access fetal brain without the impediment of an intact, mature blood-brain barrier.  These antibodies cause discrete impairments in cognitive tasks that require an intact parietal/frontal cortex in mice that were exposed to them in utero.  These studies demonstrate that maternal antibodies can alter fetal brain development and cause long lasting impairments in brain function in offspring. The spectrum of antibodies potentially damaging to the developing fetal brain must be determined as well as the conditions that might be explained by this paradigm.