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Tuesday, September 21, 2021

The brain eating itself

It is unlikely that you hear the word “microglia” very often during your classes, and it’s even less likely that you know what it is. The UC Davis Medical Investigation of Neurodevelopmental Disorders, or MIND Institute, studies microglia and has recently discovered a new role they play in our brains’ development.

Microglia are a part of the immune system for the body’s central nervous system. They are similar to macrophages (white blood cells) and are the nervous system’s primary defense against infection. Microglia also clear away dead cells and repair damage.

“Typically, microglia were thought to be stationary sentinels in the brain and were a part of the immune system,” said Stephen Noctor, an assistant professor in the Department of Psychiatry and Behavioral Sciences at UC Davis and the study’s lead author.

In other words, they were believed to be activated only when a problem occurred, but nobody discovered their role in our brains’ development until now.

At the MIND Institute, Noctor and his team found that microglia remove healthy neural progenitor cells (NPCs) by phagocytosis (eating). While this sounds counterintuitive, it means that the microglia will control the number of neurons in the brain to prevent brain overgrowth.

“We used antibody stains to label microglial cells in the brain and saw that the majority of [them] were in the germinal zones,” Noctor said.

This means that the microglial cells were found primarily in areas of the brain active in developing new brain tissue.

“We looked for evidence of interactions between the cells and found many instances in the developing monkey brain in which microglia appeared to be engulfing NPCs,” said Christopher Cunningham, a neuroscience Ph.D. candidate at UC Davis. “We also found instances where there were small bits of NPCs inside of microglial cells, suggesting that the microglia had engulfed the NPCs and then degraded them as they would degrade a pathogen.”

In the brain’s productive zone, NPCs produce neurons during development, but too many or too few neurons can lead to serious consequences. Too many and your neurons start to compete with each other for resources in your brain, creating connectional problems. Too few neurons and your brain will not function normally.

“Since many neurodevelopmental disorders, including autism and schizophrenia, involve alterations in microglial function and the number of neurons, we were intrigued by the possible link between this developmental phenomenon and the etiologies of these disorders,” Cunningham said.

After establishing that the microglia will eat healthy NPCs, the researchers’ next goal was to determine if changing the activity level of microglial cells could lead to a different amount of neurons in the brain.

Autistic children have been found to have larger brains on average, and schizophrenia patients have less-than-average grey matter. This is a significant investigative path to take, since manipulating microglial activity could, with extensive study, be a useful treatment or cure for these conditions.

The researchers also studied how microglial cells functioned in pregnant mothers and their unborn offspring by exposing the mother to different bacterial diseases, since these can affect microglial activity in the developing offspring.

“Schizophrenia has been linked to mothers having the flu during their pregnancy,” said Verónica Martínez-Cerdeño of UC Davis and Shriner’s Hospitals for Children-Northern California.

Using a rat model, the researchers exposed one group of rat mothers to bacterial lipopolysaccharide (LPS), and exposed another mother group to the antibiotic, doxycycline (Dox).

Researchers found that infant rats exposed to LPS had heightened microglial activity, and therefore 20 to 40 percent fewer NPCs. The group exposed to Dox had reduced microglial activity and about 20 percent more NPCs. The different numbers of NPCs continued well after birth for the offspring. The prevailing theory is that the mother’s living conditions affect the offspring’s microglial activity.

“We also made slice cultures in which we labeled the NPCs with one fluorescent label and microglial cells with another fluorescent label and then watched their interaction in real time on a microscope. Watching the cells provided many instances in which microglial cells would contact an NPC, and then would quickly engulf and degrade the NPC,” Cunningham said. “In most instances, contact between a microglial cell and an NPC would represent a ‘kiss of death’ for the NPC.”

Yet there is still more to study about these microglia and the reasons behind their behavior.

“We still want to find the signal that the NPCs give off to the microglia, the ‘eat me’ signal,” Martínez-Cerdeño said.

This can lead to a better understanding of why the microglia actually consume and destroy healthy NPCs, which can eventually lead to understanding neurodevelopmental disorders and how to prevent, and treat them, in the future.

KELLY MITCHELL can be reached at science@theaggie.org.

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