Maternofetal transfer of human NMDAR-antibodies leads to cortical network defect in adolescence

Abstract

Anti-N-methyl-D-aspartate-receptor IgG-antibodies (NMDAR-Ab) can be detected in up to 1% of the healthy population. Because maternal IgG can cross the placental barrier during pregnancy, these antibodies may influence fetal neurodevelopment. Using a mouse model of maternofetally transferred human NMDAR-Ab, we asked whether in utero exposure impacts functional brain dynamics later in life. We conducted two-photon calcium imaging and fMRI in adolescent mice, to evaluate both local and global neuronal network integrity. At the microcircuit scale, NMDAR-Ab exposed offspring exhibited lower spontaneous activity, reduced firing variability, and reduced orientation selectivity upon visual stimulation. Globally, fMRI revealed a selective bilateral functional hypoconnectivity of the entorhinal-hippocampal pathway while overall functional connectivity is unaffected. Together, our data indicates that maternal-fetal transfer of NMDAR-Ab leads to a lasting impairment in sensory processing and memory-routing circuits, revealing a vulnerability of the developing fetal brain to maternal autoantibodies.