The choroid plexus: A conduit for prenatal inflammation?
These tiny fronds of tissue protect the developing brain -- but may also
pass on inflammation from the mother

Date:
October 9, 2020
Source:
Boston Children's Hospital
Summary:
New work offers an unprecedented real-time view of the choroid
plexus in a mouse model, providing a glimpse of how disturbances of
the mother's immune system during pregnancy disrupt the developing
brain.



FULL STORY ========================================================================== Floating in fluid deep in the brain are small, little understood fronds of tissue. Two new studies reveal that these miniature organs are a hotbed
of immune system activity. This activity may protect the developing
brain from infections and other insults -- but may also contribute to neurodevelopmental disorders like autism.


========================================================================== "There is a correlation between maternal illness during pregnancy and
autism, and we wanted to investigate how this is happening," says Maria Lehtinen, PhD, a neurobiologist at Boston Children's Hospital who led
both studies. "It's a very challenging process to study in the lab." The Lehtinen laboratory, part of Boston Children's Department of Pathology,
is one of the few in the world to study the choroid plexus. Anchored
in each of four channels in the brain called ventricles, the choroid
plexus produces the cerebrospinal fluid (CSF) that bathes the brain and
spinal cord. Lehtinen has shown that the choroid plexus regulates brain development, by secreting instructive cues into the CSF, and provides
a protective brain barrier in early life, preventing unwanted cells or molecules in the blood circulation from freely entering the brain.

But what happens when that barrier is challenged? The lab's new work
offers an unprecedented real-time view of the choroid plexus in a mouse
model, providing a glimpse of how disturbances of the mother's immune
system during pregnancy disrupt the developing brain. It shows that the
choroid plexus can act as a conduit for inflammation, which can result
from maternal infection, stress from the environment, and other factors.

A window on the choroid plexus Because it is so deep in the brain,
the choroid plexus is normally very difficult to view. The first study, published in Neuron, built special imaging tools to capture the action
of cells in and around the choroid plexus in adult mice.



==========================================================================
Led by Frederick Shipley, PhD, Neil Dani, PhD, Lehtinen, and Mark
Andermann, PhD, at Beth Israel Deaconness Medical Center, the researchers carefully removed part of the skull bone and inserted a piece of clear plexiglass, creating a "skylight" into the brain. Using live two-photon imaging, which provides three-dimensional views of deep tissues, they
were able to observe the choroid plexus in real time. They tracked
the movements of immune cells, monitored changes in calcium (a proxy
for cellular activity), and measured the secretions of cells in the
choroid plexus.

The choroid plexus, inflammation, and the developing brain The second
study, published today in Developmental Cell and led by Jin Cui, PhD,
applied similar techniques to observe the effects of maternal inflammation
on the brains of embryonic mice. To mimic maternal inflammation,
the team introduced a molecular messenger known as a cytokine to
artificially trigger an inflammatory immune response into the embryos'
brains, then carefully placed the embryos in an imaging chamber and
conducted two-photon imaging of their brains through a tiny "skylight."
"We wanted to see how the maternal immune response is propagated into
the brain, and how the choroid plexus responds to external insults during
early development," says Cui.

The mock maternal inflammation was enough to draw immune cells known as macrophages to the embryo's choroid plexus. Imaging showed the cells
conducting active "surveillance" in the choroid plexus even in this
early embryonic stage.



==========================================================================
"The embryonic brain is very small, so it's hard to get good resolution,
but we could see macrophages moving and extending little arms as
if sampling their environment," says Lehtinen. "This has never been
captured before." Markers of future autism? The team also found an
increase in inflammatory signals, particularly CCL2, in the embryonic
CSF, and saw evidence that those signals were produced by immune cells
at the choroid plexus.

"Many of these markers, including CCL2, are also upregulated in autism patients," notes Cui.

Further experiments showed that CCL2, on its own, was sufficient to
recruit and activate immune cells at the choroid plexus. Looking at
tissue specimens, the team saw evidence that macrophages had breached the choroid plexus barrier, crossing into the CSF from specific "hotspots"
at the tips of the choroid plexus.

"We have added evidence that the inflammatory response perturbs the
development of the brain," says Cui. "Previous studies from others have
shown that maternal inflammation causes brain malformations in mouse
models very early in life, and similar malformations can be seen in some
autism patients." A treatment to protect the brain? In some of their experiments, the researchers observed patches of brain disorganization
after the mice were born. But of course, much more work is needed to
connect the dots from maternal inflammation to the choroid plexus to
disorders like autism. Even more work would be needed to translate that knowledge into treatment.

"The goal would be to see if preventing the breaching of the choroid
plexus barrier could slow or prevent the progression of disease in
the brain," says Lehtinen. "That will involve collaborating with many
different groups in multiple fields, as well as further advances in
imaging technology that are currently underway."

========================================================================== Story Source: Materials provided by Boston_Children's_Hospital. Original written by Nancy Fliesler. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Jin Cui, Frederick B. Shipley, Morgan L. Shannon, Osama
Alturkistani,
Neil Dani, Mya D. Webb, Arthur U. Sugden, Mark L. Andermann,
Maria K.

Lehtinen. Inflammation of the Embryonic Choroid Plexus Barrier
following Maternal Immune Activation. Developmental Cell, 2020;
DOI: 10.1016/ j.devcel.2020.09.020 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201009114204.htm

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