Maternofetal transfer of human NMDAR antibodies leads to cortical network defect in the adult

Abstract IgG antibodies that bind to the N-methyl-D-aspartate receptors (NMDAR-Ab) can be detected in up to 1 % of healthy individuals. This suggests that a considerable subgroup of pregnant women is at risk of transferring NMDAR-antibodies to the fetus. We ask whether a transient in utero exposure to human NMDAR-Ab can lead to neural network defects in adulthood. In mouse model of maternofetally transferred human NMDAR-Ab, at P51, corresponding to early adulthood in humans, we conducted two-photon calcium imaging in awake behaving mice. We found that microcircuits in NMDAR-Ab exposed mice exhibited a lower spontaneous activity and increased bursty firing. Upon visual stimulation, neurons in NMDAR-Ab exposed mice had a higher orientation selectivity. In NMDAR-Ab exposed mice, a large fraction of neurons active upon visual stimulation did not fire spontaneously, and vice versa . This dissociation is in sharp contrast to the operational principles in healthy networks, in which the majority of all neurons were co-active. These findings suggest that transient in utero exposure to NMDAR-Ab shifts cortical microcircuits to a maladaptive state persisting into adulthood, characterized by a dissociation between spontaneous and visually evoked activity. Such dissociation has long been hypothesized to play a role in the development of psychosis.