RT Journal Article
SR Electronic
T1 Placental transfer of NMDAR antibodies causes reversible alterations in mice
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e915
DO 10.1212/NXI.0000000000000915
VO 8
IS 1
A1 Anna García-Serra
A1 Marija Radosevic
A1 Anika Pupak
A1 Veronica Brito
A1 José Ríos
A1 Esther Aguilar
A1 Estibaliz Maudes
A1 Helena Ariño
A1 Marianna Spatola
A1 Francesco Mannara
A1 Marta Pedreño
A1 Bastien Joubert
A1 Silvia Ginés
A1 Jesús Planagumà
A1 Josep Dalmau
YR 2021
UL http://nn.neurology.org/content/8/1/e915.abstract
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