PT  - JOURNAL ARTICLE
AU  - Anna García-Serra
AU  - Marija Radosevic
AU  - Anika Pupak
AU  - Veronica Brito
AU  - José Ríos
AU  - Esther Aguilar
AU  - Estibaliz Maudes
AU  - Helena Ariño
AU  - Marianna Spatola
AU  - Francesco Mannara
AU  - Marta Pedreño
AU  - Bastien Joubert
AU  - Silvia Ginés
AU  - Jesús Planagumà
AU  - Josep Dalmau
TI  - Placental transfer of NMDAR antibodies causes reversible alterations in mice
AID  - 10.1212/NXI.0000000000000915
DP  - 2021 Jan 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e915
VI  - 8
IP  - 1
4099  - http://nn.neurology.org/content/8/1/e915.short
4100  - http://nn.neurology.org/content/8/1/e915.full
SO  - Neurol Neuroimmunol Neuroinflamm2021 Jan 01; 8
AB  - Objective To determine whether maternofetal transfer of NMDA receptor (NMDAR) antibodies has pathogenic effects on the fetus and offspring, we developed a model of placental transfer of antibodies.Methods Pregnant C57BL/6J mice were administered via tail vein patients' or controls' immunoglobulin G (IgG) on days 14–16 of gestation, when the placenta is able to transport IgG and the immature fetal blood-brain barrier is less restrictive to IgG crossing. Immunohistochemical and DiOlistic (gene gun delivery of fluorescent dye) staining, confocal microscopy, standardized developmental and behavioral tasks, and hippocampal long-term potentiation were used to determine the antibody effects.Results In brains of fetuses, patients' IgG, but not controls' IgG, bound to NMDAR, causing a decrease in NMDAR clusters and cortical plate thickness. No increase in neonatal mortality was observed, but offspring exposed in utero to patients' IgG had reduced levels of cell-surface and synaptic NMDAR, increased dendritic arborization, decreased density of mature (mushroom-shaped) spines, microglial activation, and thinning of brain cortical layers II–IV with cellular compaction. These animals also had a delay in innate reflexes and eye opening and during follow-up showed depressive-like behavior, deficits in nest building, poor motor coordination, and impaired social-spatial memory and hippocampal plasticity. Remarkably, all these paradigms progressively improved (becoming similar to those of controls) during follow-up until adulthood.Conclusions In this model, placental transfer of patients' NMDAR antibodies caused severe but reversible synaptic and neurodevelopmental alterations. Reversible antibody effects may contribute to the infrequent and limited number of complications described in children of patients who develop anti-NMDAR encephalitis during pregnancy.BBB=blood-brain barrier; CBA=cell-based assay; fEPSP=field excitatory postsynaptic potential; GEE=generalized estimated equation; GLM=generalized linear model; IgG=immunoglobulin G; LTP=long-term potentiation; NMDAR=NMDA receptor; NMDAR-ab=NMDAR antibody; NOL=novel object location; PD=postnatal day; PPI=prepulse inhibition; PSD95=postsynaptic density protein 95