Immune cells (green) on the mouse choroid plexus with red blood vessels. Photo credit: Shipley et al., Neuron 2020, 10.1016 / j.neuron.2020.08.024

In the fluid deep in the brain, there are small, little-understood fronds of tissue. Two new studies show that these miniature organs are a breeding ground for immune system activity. This activity can protect the developing brain from infection and other insults – but it can also contribute to neurodevelopmental disorders like autism.

“There’s a link between maternal illnesses during pregnancy and autism, and we wanted to study how it happens,” says Maria Lehtinen, Ph.D., neurobiologist at Boston Children’s Hospital who led both studies. “It is a very challenging process to study in the laboratory.”

The Lehtinen Laboratory, part of the Boston Department of Children’s Pathology, is one of the few in the world that examines the choroid plexus. The choroid plexus is anchored in each of the four channels in the brain called the ventricles. It produces the cerebrospinal fluid (CSF), which bathes the brain and spinal cord. Lehtinen has shown that the choroid plexus regulates brain development by secreting instructive clues into CSF, and provides a protective brain barrier in early life that prevents unwanted cells or molecules in the bloodstream from freely entering the brain.

But what happens when that barrier is challenged? The lab’s new work provides an unprecedented real-time view of the choroid plexus in a mouse model and provides insight into how disorders 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 that can result from maternal infections, environmental stress, and other factors.

A window to the choroid plexus

Because it is so deep in the brain, the choroid plexus is usually very difficult to see. In the first study published in Neuron, special imaging tools were developed to assess the effects of cells in and around the choroid plexus in adult mice.

Under the direction of Dr. Frederick Shipley, Dr. Neil Dani, Dr. Lehtinen and Dr. Mark Andermann of the Beth Israel Deaconness Medical Center, the researchers carefully removed part of the skull bone and placed a piece of it in clear Plexiglas, which creates a “skylight” in the brain. Using live two-photon imaging, which provides three-dimensional views of deep tissue, 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 cell activity), and measured secretions from 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, Ph.D., used similar techniques to monitor the effects of maternal inflammation on the brains of embryonic mice. To mimic the mother’s inflammation, the team introduced a molecular messenger known as a cytokine to artificially trigger an inflammatory immune response in the embryo’s brain. He then carefully placed the embryos in an imaging chamber and performed two-photon imaging of their brains through a tiny “skylight.”

“We wanted to see how the maternal immune response spreads in the brain and how the choroid plexus reacts to external insults during early development,” says Cui.

The Choroid Plexus: A Channel for Antenatal Inflammation?

The arrowheads show immune cells (red, macrophages; green, leukocytes) that have been collected at “hotspots” in the choroid plexus and from which they appear to enter the cerebrospinal fluid. Photo credit: Jin Cui, PhD, Boston Children’s Hospital

The apparent maternal inflammation was enough to pull immune cells known as macrophages into the embryo’s choroid plexus. The imaging showed that the cells were already actively “monitoring” the choroid plexus at this early embryonic stage.

“The embryonic brain is very small, so it is difficult to get a good resolution, but we could see macrophages moving and little arms stretching out as if they were examining their surroundings,” says Lehtinen. “This has never been recorded before.”

Markers for Future Autism?

The team also found an increase in inflammatory signals, especially CCL2, in embryonic CSF and saw evidence that these signals were generated by immune cells in the choroid plexus.

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

Further experiments showed that CCL2 alone was sufficient to recruit and activate immune cells at the choroid plexus. When examining tissue samples, the team saw evidence that macrophages had broken through the barrier of the choroid plexus and entered the CSF from certain “hotspots” at the tips of the choroid plexus.

“We added evidence that the inflammatory response interferes with brain development,” says Cui. “Previous studies by 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 required to link the points from the maternal inflammation to the choroid plexus to disorders such as autism. More work would be needed to translate this knowledge into treatment.

“The goal would be to see if preventing the choroid plexus barrier from breaking could slow or prevent disease progression in the brain,” says Lehtinen. “This includes working with many different groups in different fields, as well as further advances in imaging technology that are currently underway.”

An area of ​​the brain where tumor cells protect against chemotherapy for childhood leukemia

More information:
Development Cell (2020). DOI: 10.1016 / j.devcel.2020.09.020

Neuron (2020). DOI: 10.1016 / j.neuron.2020.08.024

Provided by Boston Children’s Hospital

Quote: The Choroid Plexus: A Channel for Antenatal Inflammation? (2020, October 9) Retrieved October 9, 2020 from

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