A New Prenatal Driver of Neurodevelopmental Disorders

The Context: The choroid plexus is a brain structure that makes cerebrospinal fluid (CSF): liquid that bathes the brain and spinal cord to form a protective barrier and assist with nourishment and waste removal.  The choroid plexus can also influence brain development, and while there is a correlation between maternal illness during pregnancy and developmental disorders like autism, scientists do not fully understand this link.

The Study: The choroid plexus plays a major role in immune system activity, according to studies in Developmental Cell and Neuron by NYSCF – Robertson Neuroscience Investigator Maria Lehtinen, PhD, of Boston Children’s Hospital. Dr. Lehtinen’s team found that the choroid plexus can act as a conduit for inflammation when a pregnant mother is stressed, has an infection, or is otherwise challenged, potentially contributing to developmental disorders such as autism in offspring.

The Importance: This study illuminates a previously unknown role of the choroid plexus in inflammation and suggests that this structure could be a driver of neurodevelopmental disorders prenatally. Understanding this connection could help researchers develop new therapies to potentially intervene in progression of these disorders.

The functions of the choroid plexus remains a bit of a mystery, as studying the tiny brain structure can be difficult and few labs focus on it.

“There is a correlation between maternal illness during pregnancy and autism, and we wanted to investigate how this is happening,” said Dr. Lehtinen, a neurobiologist at Boston Children’s Hospital in a press release. “It’s a very challenging process to study in the lab.”

Dr. Lehtinen’s team took a look at how changes in a mother’s immune system during pregnancy in mice can affect fetal brain development, focusing on the choroid plexus.

A Skylight in the Skull

The choroid plexus is typically hard to image, so in the team’s first study, published in Neuron in collaboration with NYSCF – Robertson Neuroscience Investigator Claire Wyart, PhD (The Brain & Spine Institute, France), the scientists built an imaging tool to look at behavior of cells around the choroid plexus in adult mice.

The team fitted a ‘skylight’ in the mouse’s head by removing a part of the skull and replacing it with plexiglass. With a technique called live two-photon imaging, the researchers could then study the choroid plexus of awake mice in 3D and in real time, examining the immune cells’ activity and secretions.

How the Embryonic Choroid Plexus Responds to Maternal Immune Activation 

In the second study, published in Developmental Cell, the team used their new imaging technique to observe how inflammation – a hallmark response to infection or other immune challenges – in a pregnant mother affected their embryonic offspring. 

“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,” said first author Jin Cui, PhD.

When activating the maternal immune system, the team observed a corresponding inflammatory response in the embryo, that led to the migration of immune cells called macrophages to the choroid plexus. This highlighted the protective role of the developing choroid plexus in handling external immune challenges.

“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,” noted Dr. Lehtinen. “This has never been captured before.”

A Possible Link Between Inflammation in the Developing Brain and Autism

The embryonic inflammatory response included elevation of a cytokine called CCL2 in the embryonic CSF, seemingly coming from immune cells surrounding the choroid plexus.

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

The team then investigated whether CCL2 alone could trigger an immune response in the choroid plexus, and indeed observed immune cells aggregating and activating at the choroid plexus. Macrophages were also infiltrating the CSF from ‘hotspots’ at the ends of the choroid plexus, and the researchers found evidence of brain disorganization in the newborn mice.

“We have added evidence that the inflammatory response perturbs the development of the brain,” said Dr. 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.”

More work is needed to determine a link between maternal inflammation and autism via the choroid plexus and to understand whether this association may offer opportunities for preventing autism or other 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,” said Dr. Lehtinen. “That will involve collaborating with many different groups in multiple fields, as well as further advances in imaging technology that are currently underway.”

 Journal Articles:

Inflammation of the Embryonic Choroid Plexus Barrier following Maternal Immune Activation
Jin Cui, Frederick B. Shipley, Morgan L. Shannon, Osama Alturkistani, Neil Dani, Mya D.Webb, Arthur U.Sugden, Mark L.Andermann, Maria K.Lehtinen. Developmental Cell. 2020. DOI: https://doi.org/10.1016/j.devcel.2020.09.020

Tracking Calcium Dynamics and Immune Surveillance at the Choroid Plexus Blood-Cerebrospinal Fluid Interface
Frederick B. Shipley, Neil Dani, Huixin Xu, Christopher Deister, Jin Cui, Joshua P. Head, Cameron Sadegh, Ryann M. Fame, Morgan L. Shannon, Vanessa I. Flores, Thomas Kishkovich, Emily Jang, Eric M.Klein, Glenn J. Goldey, Kangmin He, Yong Zhang, Michael J. Holtzman, Tomas Kirchhausen, Claire Wyart, Christopher I.Moore, Mark L.Andermann, Maria K.Lehtinen. Neuron. 2020. DOI: https://doi.org/10.1016/j.neuron.2020.08.024

Cover image: Immune cells (in green) on the mouse choroid plexus, with blood vessels in red.

Photo credit: Shipley et al., Neuron 2020, https://doi.org/10.1016/j.neuron.2020.08.024