Placental transfer of NMDAR antibodies causes reversible alterations in mice
Altres ajuts: Project Integrative of Excellence (PIE 16/00014); Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER; #CB15/00010); "La Caixa" Foundation (ID 100010434, under the agreement LCF/PR/HR17/52150001); The Safra Foundation (J.D.), and Fundació CELLEX (J.D.); Centres de Recerca de Catalunya (CERCA) program by La Generalitatde Catalunya (J.R.); Pla Estratègic de Recerca i Innovació en Salut (PERIS, SLT002/16/00346, J.P.); Basque Government Doctoral Fellowship Program (PRE_ 2019_1_0255; E.M.) ; 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. 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. 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. In ...