Summary: Embryonic damage caused by autoantibodies is implicated in a range of behavioral and psychological disorders, including schizophrenia, autism, and ADHD.
Dysfunctions in the maternal immune system that occur during pregnancy could possibly lead to impaired brain development in the unborn child. This is suggested by studies by the German Center for Neurodegenerative Diseases (DZNE) and Charite – Universitaetsmedizin Berlin, which are based on laboratory experiments and additional findings in humans. According to these studies, embryonic damage due to so-called autoantibodies could be a previously unnoticed cause of behavioral disorders that occur in diseases such as autism, schizophrenia, and ADHD. The research results are published in the journal Annals of Neurology.
During pregnancy, antibodies from the mother’s blood constantly enter the embryonic circulation via the umbilical cord to protect the developing child from infection. However, not all maternal antibodies are directed against foreign substances and serve to defend from pathogens. Some antibodies – known as autoantibodies – attack the body’s own tissues. They may thus cause damage that can manifest, for example, as autoimmune diseases. Just like the beneficial antibodies, a pregnant woman passes on potentially harmful autoantibodies to her unborn child. This could promote the development of behavioral disorders in the child, as recent studies in animal models suggest. Initial data from studies in humans support these findings.
The current study, led by Dr. Harald Pruess from the DZNE’s Berlin site and the Department of Neurology with Experimental Neurology at the Charite, focused on an autoantibody that targets a specific protein on the surface of brain cells. This molecule, known as ‘NMDA receptor’, is essential for the interconnection of neurons and normal brain development. “The NMDA receptor antibody is a relatively common autoantibody. Data from blood donations suggest that up to one percent of the general population may carry this particular autoantibody in their blood. The reasons for this are largely unclear,” said Pruess. If this autoantibody reaches the brain, serious inflammations can arise. However, most carriers are free of such symptoms because the blood-brain barrier – a filtering tissue that surrounds the brain’s blood vessels – is usually hardly penetrable for antibodies. Unless this barrier is damaged or, as with an embryo in early pregnancy, not yet fully developed.
“We investigated the hypothesis that NMDA receptor antibodies reach the brain of the embryo and cause subtle but lasting impairments during this important phase of brain development,” explained Pruess. Indeed, in mice, large quantities of maternal autoantibodies were found to reach the brain of the embryo. This resulted in a reduction of NMDA receptors, altered physiological functions, and impaired neuronal development. The offspring showed abnormalities in behavior and some areas of their brains were smaller compared to healthy animals. “This hitherto unknown form of pregnancy-associated brain diseases is reminiscent of psychiatric disorders caused by rubella or chickenpox pathogens. These types of infections also have a temporary effect on the brain that can have lifelong consequences,” said Pruess.
Findings in humans
In humans, initial analyses of data from a group of 225 mothers suggest that these autoantibodies occur more frequently in women who have a child with a neurodevelopmental disorder or psychiatric disease. The mothers seem to be protected by the blood-brain barrier. “Further studies will be needed in order to confirm the link between maternal NMDA receptor antibodies and human psychiatric disorders in humans,” Pruess emphasized. “However, should future research results confirm our hypothesis, tests for such antibodies in pregnant women would have to be included in prenatal screenings. Where necessary, this would allow to initiate treatments to remove the autoantibodies in order to prevent the child from suffering potentially life-long adverse health effects.”
The current results may explain why previous studies have failed to demonstrate a clear link between NMDA receptor antibodies and psychiatric diseases such as schizophrenia. In newborns, the antibodies transferred by the mother are broken down within a matter of weeks. Most patients in existing studies were young adults. Therefore, when the testing for these autoantibodies took place, they had long since disappeared.
About this neuroscience research article
Source: DZNE Media Contacts: Harald Pruess – DZNE Image Source: The image is in the public domain.
Human gestational NMDAR autoantibodies impair neonatal murine brain function
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 240μg 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.