| Autor: |
Jurek, Betty, Chayka, Mariya, Kreye, Jakob, Lang, Katharina, Kraus, Larissa, Fidzinski, Pawel, Kornau, Hans���Christian, Dao, Le���Minh, Wenke, Nina K., Long, Melissa, Rivalan, Marion, Winter, York, Leubner, Jonas, Herken, Julia, Mayer, Simone, Mueller, Susanne, Boehm���Sturm, Philipp, Dirnagl, Ulrich, Schmitz, Dietmar, K��lch, Michael, Pr��ss, Harald |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Popis: |
Objective: Maternal autoantibodies are a risk factor for impaired brain development in offspring. Antibodies (ABs) against the NR1 (GluN1) subunit of the N-methyl-d-aspartate receptor (NMDAR) are among the most frequently diagnosed anti-neuronal surface ABs, yet little is known about effects on fetal development during pregnancy. Methods: We established a murine model of in utero exposure to human recombinant NR1 and isotype-matched nonreactive control ABs. Pregnant C57BL/6J mice were intraperitoneally injected on embryonic days 13 and 17 each with 240��g of human monoclonal ABs. Offspring were investigated for acute and chronic effects on NMDAR function, brain development, and behavior. Results: Transferred NR1 ABs enriched in the fetus and bound to synaptic structures in the fetal brain. Density of NMDAR was considerably reduced (up to -49.2%) and electrophysiological properties were altered, reflected by decreased amplitudes of spontaneous excitatory postsynaptic currents in young neonates (-34.4%). NR1 AB-treated animals displayed increased early postnatal mortality (+27.2%), impaired neurodevelopmental reflexes, altered blood pH, and reduced bodyweight. During adolescence and adulthood, animals showed hyperactivity (+27.8% median activity over 14 days), lower anxiety, and impaired sensorimotor gating. NR1 ABs caused long-lasting neuropathological effects also in aged mice (10 months), such as reduced volumes of cerebellum, midbrain, and brainstem. Interpretation: The data collectively support a model in which asymptomatic mothers can harbor low-level pathogenic human NR1 ABs that are diaplacentally transferred, causing neurotoxic effects on neonatal development. Thus, AB-mediated network changes may represent a potentially treatable neurodevelopmental congenital brain disorder contributing to lifelong neuropsychiatric morbidity in affected children. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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