The choroid plexus (ChP), located within the ventricles of the brain, produce the cerebrospinal fluid (CSF). It plays a central role in regulating inflammatory cells in the central nervous system (CNS), as well as in monitoring the synthesis, composition, and circulation of cerebrospinal fluid. Although the choroid plexus has been found to regulate brain development by secreting cues in the CSF and providing a protective barrier in early life—two studies have revealed that when a mother’s immune system is disrupted during pregnancy, the choroid plexus may act as a channel for prenatal inflammation, which may result in neurodevelopmental disorders such as autism.

The first study provided a clearer picture of the choroid plexus. The study, “Tracking Calcium Dynamics and Immune Surveillance at the Choroid Plexus Blood-Cerebrospinal Fluid Interface,” was published in Neuron and led by Frederick Shipley, PhD, research fellow, Boston Children’s Hospital; Neil Dani, PhD, postdoctoral researcher, Boston Children’s Hospital; and Mark Andermann, PhD, principal investigator and associate professor of medicine at Beth Israel Deaconness Medical Center.

The Lehtinen Laboratory, part of Boston Children’s Department of Pathology, studying the choroid plexus, decided to investigate what happens when the barrier is challenged. Using a mouse model, they built special imaging tools to capture the action of cells in and around the choroid plexus in adult mice.

The researchers removed part of the skull bone and inserted a piece of clear Plexiglas. Using live two-photon imaging, the researchers were able to observe the choroid plexus in real time. They tracked the movements of immune cells, monitored changes in calcium, and measured the secretions of cells in the choroid plexus.

“Here, we develop imaging tools to interrogate these functions in adult lateral ventricle ChP in whole-mount explants and in awake mice,” the researchers wrote. “By imaging epithelial cells in intact ChP explants, we observed calcium activity and secretory events that increased in frequency following delivery of serotonergic agonists. Using chronic two-photon imaging in awake mice, we observed spontaneous subcellular calcium events as well as strong agonist-evoked calcium activation and cytoplasmic secretion into CSF.”

Immune cells (in green) on the mouse choroid plexus, with blood vessels (in red). [Shipley et al., Neuron 2020,]
The second study, “Inflammation of the Embryonic Choroid Plexus Barrier following Maternal Immune Activation,” published in Developmental Cell and led by Jin Cui, PhD, postdoctoral researcher, Boston Children’s Hospital, applied similar methods to observe the effects of maternal inflammation on the brains of embryonic mice.

The researchers used cytokine to artificially trigger an inflammatory immune response into the mice embryos’ brains. They then placed the embryos in an imaging chamber and conducted two-photon imaging of their brains.

“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,” stated Cui.

“Our findings demonstrate that during early brain development, inflammation leads to ChP immune cell accumulation and loosens the ChP barrier. These findings extend our view of the gatekeeper role of embryonic ChP for not only as a gatekeeper regulating CNS entry of peripheral nutrients, toxins, and xenobiotics but also entry of peripheral immune cells,” noted the researchers.

The arrowheads show immune cells (red, macrophages; green, leukocytes) gathered at “hotspots” in the choroid plexus, from which they appear to enter the cerebrospinal fluid. [Jin Cui, PhD, Boston Children’s Hospital]
“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,” wrote the researchers. “This has never been captured before.”

The researchers also found an increase in inflammatory signals, CCL2 produced by immune cells at the choroid plexus. “Many of these markers, including CCL2, are also upregulated in autism patients,” noted Cui. “We have added evidence that the inflammatory response perturbs the development of the brain. 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.”

Further observation in some of their experiments revealed patches of brain disorganization after the mice were born, but further study is needed to connect the dots of maternal inflammation, choroid plexus, and neurodevelopmental disorders.

Both studies are a step forward in understanding the developing brain and the immune system. Their findings may lead to further studies into connecting the dots and further advances in imaging technology and treatments for neurodevelopmental disorders.

“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,” according to the researchers. “That will involve collaborating with many different groups in multiple fields, as well as further advances in imaging technology that are currently underway.”

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