The immune responses of female mice before pregnancy can predict how likely their offspring will be to have behavioral deficits if the mother's immune system is activated during pregnancy, according to a new mouse study. Researchers found that measuring a mouse's inflammatory response to a viral mimic before pregnancy allowed them to determine if the offspring would develop problems if the mother was exposed to the mimic during gestation. This could help identify pregnancies that are more at risk from maternal infections and lead to ways to prevent neurodevelopmental disorders in children.

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New insight on maternal infections and neurodevelop-
mental disorders
Mouse study predicts why some mothers may be susceptible
May 4, 2020
University of California - Davis
The immune responses of a female mouse before pregnancy can predict how likely her
offspring are to have behavioral deficits if the immune system is activated during preg‐
nancy. The findings could help resolve what role serious infections during pregnancy
play in the development of conditions such as autism and schizophrenia.
FULL STORY
The immune responses of a female mouse before
pregnancy can predict how likely her offspring are to
have behavioral deficits if the immune system is acti‐
vated 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 McAl‐
lister, director of the Center for Neuroscience and senior author on
the paper. Most pregnancies are resilient, she said. 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,"
she said. "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."
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
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2. 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 sys‐
tem recognizes poly (I:C) as if it were a virus and triggers an im‐
mediate 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 ab‐
normalities, 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, suggest‐
ed 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.
"People assume that their mice are all the same, but there is
clearly a wide range of baseline immunoreactivity," McAllister
said. 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," she said.
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 neu‐
rodevelopmental disorders.
"The next steps are to figure out what it is that is different about
those mice," McAllister said. "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 off‐
spring. 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."
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3. Cite This Page:
University of California - Davis. "New insight on maternal infec‐
tions and neurodevelopmental disorders: Mouse study predicts
why some mothers may be susceptible." ScienceDaily. Science‐
Daily, 4 May 2020.
<www.sciencedaily.com/releases/2020/05/200504165703.htm>.
Secondly, it 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.
Story Source:
Materials provided by University of California - Davis. Original
written by Andy Fell. Note: Content may be edited for style and
length.
Journal Reference:
1. Myka L. Estes, Kathryn Prendergast, 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 McAllis‐
ter. Baseline immunoreactivity before pregnancy and
poly(I:C) dose combine to dictate susceptibility and re‐
silience of offspring to maternal immune activation. Brain,
Behavior, and Immunity, 2020; DOI: 10.1016/j.bbi.2020.04.061
MLA APA Chicago
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