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Developmental Biology - Brain Development

Mom's Infections May Affect Fetal Brain Disorders

Maternal infections and neurodevelopmental disorders may be linked...

The immune response of a female mouse before pregnancy can predict how likely her offspring have behavioral deficits if the immune system is activated during pregnancy, according to researchers from the Center for Neuroscience at the University of California, Davis. The findings, published April 23 in the journal Brain, Behavior, and Immunity, could help resolve what role serious infections during pregnancy play in the later development of conditions such as autism and schizophrenia in offspring.

Both genetics and a variety of environmental risk factors are thought to play a role in mental illness, said Professor Kim McAllister, director of the Center for Neuroscience and senior author on the paper. Most pregnancies are resilient, she explains. Although the risk from maternal immune activation is low, it could provide a way in to the underlying problems that lead to schizophrenia or autism.
"We don't have a good handle on what causes these diseases. But, maternal infection is a risk factor that we know contributes. So, our research focuses on how to predict which pregnancies are at risk and discover new ways to intervene and prevent disease in offspring."

A. Kimberley Mc Allister PhD, Professor, Director, Center for Neuroscience, and senior author on the paper.

The first evidence for a role for maternal infection in mental and developmental disorders came from the influenza epidemic of 1918, McAllister said. Epidemiological studies 15 to 20 years later of children who were in gestation at the time showed an increase in these disorders. Other evidence comes from animal studies.

Mouse Model of Immune Activation
Apart from influenza, a wide variety of viruses and bacteria have been implicated in maternal immune activation. So the effect is more likely due to the mother's reaction to infections than with the infectious organism itself.

To reproduce this in mice, McAllister's team doses pregnant mice with a molecule called polyinosinic:polycytidylic acid, or poly (I:C), which is double-stranded RNA, the genetic material for many viruses including influenza and coronaviruses.
The immune system recognizes poly (I:C) as if it were a virus and triggers an immediate inflammatory response, especially releasing a molecule called interleukin-6, or IL-6.

The mice continue with pregnancy and when the offspring are about 2 months old, the researchers test them for behavioral abnormalities, such as repetitive behaviors or freezing in place. One of the advantages of working with laboratory mice is that they are bred so that they are genetically very similar. That makes it easier to see the effect of particular genes or environmental risk factors.
But when graduate student Myka Estes tried to treat laboratory mice with poly (I:C), she found to her surprise that their responses varied widely, even though the mice were all of the same age and genetic background, housed in the same cages in the same conditions.

Professor Judy Van de Water, an immunologist at the UC Davis School of Medicine and part of Estes' thesis committee, suggested looking at baseline immune reactivity in the mice before they became pregnant.
When they did that, the team found that the IL-6 response of a particular mouse to poly (I:C) before it became pregnant could predict the likelihood of behavioral problems in offspring if the mouse were treated with poly (I:C) later during pregnancy.

McAllister: "People assume that their mice are all the same, but there is clearly a wide range of baseline immunoreactivity." If that baseline immunoreactivity turns out to predict resilience or susceptibility to immune activation during pregnancy. "We can dose them with poly (I:C) and look at the IL-6 response and predict which ones will have affected offspring if we treat them during pregnancy."

Basic Mechanisms and Biomarkers

That has a couple of important implications. Firstly, with a reliable model for resilience and susceptibility, researchers can start to work out what genes and proteins involved in brain development are affected by immune activation and how this could lead to neurodevelopmental disorders.
"The next steps are to figure out what it is that is different about those mice. Now that we can predict which mice are at risk, we want to determine how specific patterns of immune signaling in the mom cause distinct outcomes in offspring. We are hoping to figure out how maternal infection can lead to no problem in many pregnancies and to a range of distinct diseases in offspring from other pregnancies."

A. Kimberley Mc Allister PhD

This could lead to biomarkers for identifying pregnancies at higher risk from infections and taking steps to protect mothers by vaccination or treatment. That will likely involve further work in mice followed up with experiments in nonhuman primates before moving into human studies.
• Isogenic virgin C57BL/6 female mice exhibit an unexpectedly wide range of baseline immunoreactivity (BIR) to low dose poly(I:C)

• A combination of BIR prior to pregnancy and poly(I:C) dose during maternal immune activation (MIA) predicts susceptibility or resilience to altered repetitive behaviors and striatal protein levels in young adult offspring.

• In susceptible pregnancies, BIR prior to pregnancy predicts which distinct constellation of phenotypes arise in offspring.

• The intermediate levels of BIR and poly(I:C) dose are most detrimental to offspring, with higher BIR and poly(I:C) doses conferring resilience to measured phenotypes in offspring.

• We identify the BIR of female mice as a biomarker before pregnancy that predicts which dams will be most at risk as well as biomarkers in the brains of newborn offspring that correlate with changes in repetitive behaviors.

Despite the potential of rodent models of maternal immune activation (MIA) to identify new biomarkers and therapeutic interventions for a range of psychiatric disorders, current approaches using these models ignore two of the most important aspects of this risk factor for human disease: (i) most pregnancies are resilient to maternal viral infection and (ii) susceptible pregnancies can lead to different combinations of phenotypes in offspring. Here, we report two new sources of variability—the baseline immunoreactivity (BIR) of isogenic females prior to pregnancy and differences in immune responses in C57BL/6 dams across vendors—that contribute to resilience and susceptibility to distinct combinations of behavioral and biological outcomes in offspring. Similar to the variable effects of human maternal infection, MIA in mice does not cause disease-related phenotypes in all pregnancies and a combination of poly(I:C) dose and BIR predicts susceptibility and resilience of pregnancies to aberrant repetitive behaviors and alterations in striatal protein levels in offspring. Even more surprising is that the intermediate levels of BIR and poly(I:C) dose are most detrimental to offspring, with higher BIR and poly(I:C) doses conferring resilience to measured phenotypes in offspring. Importantly, we identify the BIR of female mice as a biomarker before pregnancy that predicts which dams will be most at risk as well as biomarkers in the brains of newborn offspring that correlate with changes in repetitive behaviors. Together, our results highlight considerations for optimizing MIA protocols to enhance rigor and reproducibility and reveal new factors that drive susceptibility of some pregnancies and resilience of others to MIA-induced abnormalities in offspring.

Myka L. Estesa; Kathryn Prendergasta; Jeremy A. MacMahon; Scott Cameron; John Paul Aboubechara; Kathleen Farrelly; Gabrielle L. Sell; Lori Haapanen; Joseph D. Schauer; Aurora Horta; Ida C.Shaffer; Catherine T. Le; Greg N. Kincheloe; Danielle John Tan; Deborah van der List; Melissa D. Bauman; Cameron S. Carter; Judy Van de Water; A. Kimberley Mc Allister.

The work was supported by grants from the Simons Foundation Autism Research Initiative, Autism Speaks, several UC Davis fellowships and awards, the NIH and by the NIH-funded Silvio O. Conte Center at UC Davis.

The American Chemical Society (ACS) is a nonprofit organization chartered by the U.S. Congress. ACS' mission is to advance the broader chemistry enterprise and its practitioners for the benefit of Earth and its people. The Society is a global leader in providing access to chemistry-related information and research through its multiple research solutions, peer-reviewed journals, scientific conferences, eBooks and weekly news periodical Chemical & Engineering News. ACS journals are among the most cited, most trusted and most read within the scientific literature; however, ACS itself does not conduct chemical research. As a specialist in scientific information solutions (including SciFinder® and STN®), its CAS division powers global research, discovery and innovation. ACS' main offices are in Washington, D.C., and Columbus, Ohio.

The authors acknowledge funding from the National Natural Science Foundation of China and the China Postdoctoral Science Foundation.

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May 6 2020   Fetal Timeline   Maternal Timeline   News

Scientists imaged a mouse brain with a new staining method that can image up to four molecular
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