- During pregnancy, various exposures such as stress and infection can cause maternal immune activation that is thought to be responsible for certain neurologic disorders in offspring
- One proposed mechanism is that microglia—resident brain immune cells that play a critical role in normal brain development—are "primed" in utero toward a pro-inflammatory phenotype, which alters synaptic pruning
- By reprogramming neonatal cord blood mononuclear cells, researchers at Massachusetts General Hospital have created patient-specific models of fetal microglia-mediated synaptic pruning
- These models are expected to permit non-invasive investigation of how maternal exposures, including SARS-CoV-2 infection, affect the fetal brain and aid development of targeted interventions to prevent neurodevelopmental morbidity
During pregnancy, various exposures such as stress and infection can cause maternal immune activation that interferes with normal brain development in the fetus. For example, there's strong evidence that some cases of autism spectrum disorder, schizophrenia and cerebral palsy are linked to maternal viral and bacterial infection.
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What causes the neurologic morbidity isn't clear. However, one theory is that microglia—resident brain immune cells that play a critical role in normal brain development—are "primed" in utero toward a pro-inflammatory phenotype. In turn, these changes alter the synaptic pruning that's an important part of fetal and neonatal development.
By adapting and extending research they did previously in adults, researchers at Massachusetts General Hospital have created personalized neonatal models of microglial priming and function. These models should allow for the identification of neonates and children most vulnerable to neurodevelopmental disorders related to a range of maternal exposures, including SARS-CoV-2.
Steven D. Sheridan, PhD, director of the Platform for Cellular Modeling of Neuropsychiatric Disease, Jessica M. Thanos, research technologist, and Roy Perlis, MD, MSc, director of the Center for Quantitative Health in the Department of Psychiatry at Mass General; Andrea G. Edlow, MD, MSc, an investigator in the Vincent Center for Reproductive Biology; and colleagues report their methods in Translational Psychiatry.
Creating and Evaluating the Models
As detailed in Nature Neuroscience and Molecular Psychiatry, Mass General researchers previously developed and validated patient-specific models of microglia-mediated synaptic pruning by reprogramming induced microglial cells from adult peripheral blood mononuclear cells.
In the current study, they adapted their methods to reprogram umbilical cord blood–derived mononuclear cells from neonates of two SARS-CoV-2 positive mothers and four uninfected mothers delivered between June 7 and July 6, 2020.
The cells were morphologically and functionally similar to microglia observed in vivo. They functioned well in an in vitro model of synaptic pruning.
Significance of the Models
These personalized assays are expected to yield novel non-invasive insights into how fetal brain development is affected by maternal exposures, including but not limited to SARS-CoV-2 infection. This will be helpful in informing risk assessments for an individual fetus.
Importantly, the models should be able to predict neurodevelopmental vulnerability at a time when there is a window for intervention. They can be used to test therapies that might prevent in utero priming of microglia toward a pro-inflammatory phenotype.
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