Microglia controls neuron production as brain develops

February 27, 2013

(Medical Xpress)—In a surprise breakthrough, researchers at the UC Davis MIND Institute and their colleagues have found that microglia remove healthy neural progenitor cells (NPCs) through phagocytosis to control neuron production during brain development. This newly discovered mechanism keeps neuron numbers in check, preventing brain overgrowth.

The discovery could open up new avenues for and lead to therapies for a variety of .

The study was published online today in the The Journal of Neuroscience.

Microglia are the immune component cell of the . Similar to , microglia provide the brain's primary defense against pathogens and , clear away dying cells and help repair neural damage. When inactive, they act as sentinels. When a problem is located, they activate and eliminate it. However, until recently, no one had realized the important roles they play in .

"We have known for some time that can undergo apoptosis, a form of , and ultimately be removed by microglia," said Stephen Noctor, assistant professor in the Department of Psychiatry and and the study's lead author. "But this is new. Microglia are actually eating healthy progenitor cells, thereby regulating the number of neurons produced in the developing brain."

During development, NPCs produce neurons in the brain's proliferative zones. However, creating too many or too few neurons can have dire consequences.

"If you have too many cells, there's only so much trophic support (brain infrastructure for cell growth and survival) to keep neurons alive," Noctor said. "All these cells competing for resources could easily throw off connectional properties, altering the way surviving neurons interact. Likewise, having too few cortical cells would have profoundly ."

Studying tissue from and rats, the researchers noted that microglia colonize the proliferative zones of the prenatal brain. The researchers labeled the microglia and NPCs with antibodies and other markers to track microglial status—whether they were resting or active—and their interactions with progenitor cells. Microglia were concentrated in the proliferative zone where NPCs proliferate and produce new neurons.

The vast majority—95 percent—of microglia in the proliferative zone were activated. Even more importantly, they were engulfing and eating NPCs. However, the team had to determine the NPC's health status. If the NPCs were dead or dying, the microglial activity would not have been unusual, as removing these cells is one of their primary functions.

conveniently provide "eat me" signals to microglia. For example, they express phosphatidylserine (PS) on their surface. The investigators found that PS-expressing cells could be found throughout the brain, but were not concentrated with microglia in the proliferative zones. Other experiments indicated that the NPCs being targeted by microglia were healthy cells.

"The progenitor cells being eaten didn't appear to be apoptotic or damaged in any way," said Dr. Noctor. "They appeared to be normal in every respect."

In addition, regional differences in the distribution of microglia point to another role for the cells. By selectively eliminating NPCs, and as a result neurons, they may contribute to the development of regional differences in brain architecture.

As time goes on, microglial cell distribution adjusts to the maturing brain. "Microglia are generated in the yolk sack and quickly become attracted to the proliferative zones in the brain, colonize that zones and have a feast," said Noctor. "However, after neurogenesis is over, they distribute throughout the brain to acquire their adult distribution. So if you look at an adult brain, there's an even distribution of microglial cells."

Having established that microglia eat healthy NPCs, the next step was to determine whether modulating their activity could alter NPC numbers. This could have profound clinical consequences. For example, a number of studies have shown that autistic children have larger brains. While there is limited evidence, at present, that microglia play a role in autism, this could be an important investigative path. In addition, this study could have implications for schizophrenia treatment.

"If a mother is exposed to a pathogen, such as influenza, in the first trimester, that increases the likelihood of schizophrenia," Noctor said. "Recent studies suggest that the schizophrenic brain has less grey matter. Together these data suggest the hypothesis that mothers might get an immune response in the first trimester, which our data shows increases the activation of microglia, and as a result microglia may take out too many in the developing brain."

To test this idea, the team treated rats with bacterial lipopolysaccharide (LPS), which generates an inflammatory response and activates microglia in prenatal brains. They also treated another group of pregnant rats with the antibiotic doxycycline (Dox), which suppresses microglial activation.

Increasing microglial activity in the LPS group significantly reduced the number of NPCs by 20 to 40 percent. Meanwhile, the Dox treatment, which inhibited the microglial activation, increased the number of NPCs by 20 percent. These changes in NPC numbers persisted well after birth.

Going a step further, the researchers used liposomal clodronate to remove microglia from the developing brain. The clodronate eliminated 90 percent of the microglia, which significantly increased the NPC population.

This direct relationship between microglial activity and neuron production could provide a clinical pathway to prevent schizophrenia and other disorders.

"We activated the microglial cells with different compounds," Noctor said. "There are also drugs on the market that deactivate microglia. We could potentially use these tools to control microglial activation in controlled studies to determine if this is a viable way to restore the brain's proper balance."

Explore further: Gardening in the brain: Specialist cells prune connections between neurons

Related Stories

Gardening in the brain: Specialist cells prune connections between neurons

July 21, 2011
Gardeners know that some trees require regular pruning: some of their branches have to be cut so that others can grow stronger. The same is true of the developing brain: cells called microglia prune the connections between ...

Study examines role of microglial cells as both defenders and fighters in the nervous system

October 16, 2012
(Medical Xpress)—In many pathologies of the nervous system, there is a common event - cells called microglia are activated from surveillant watchmen into fighters.  Microglia are the immune cells of the nervous system, ...

The Japanese traditional therapy, honokiol, blocks key protein in inflammatory brain damage

March 19, 2012
Microglia are the first line defence of the brain and are constantly looking for infections to fight off. Overactive microglia can cause uncontrolled inflammation within the brain, which can in turn lead to neuronal damage. ...

Natural process activating brain's immune cells could point way to repairing damaged brain tissue

October 21, 2012
The brain's key "breeder" cells, it turns out, do more than that. They secrete substances that boost the numbers and strength of critical brain-based immune cells believed to play a vital role in brain health. This finding ...

Recommended for you

The neural codes for body movements

July 21, 2017
A small patch of neurons in the brain can encode the movements of many body parts, according to researchers in the laboratory of Caltech's Richard Andersen, James G. Boswell Professor of Neuroscience, Tianqiao and Chrissy ...

Faulty support cells disrupt communication in brains of people with schizophrenia

July 20, 2017
New research has identified the culprit behind the wiring problems in the brains of people with schizophrenia. When researchers transplanted human brain cells generated from individuals diagnosed with childhood-onset schizophrenia ...

Scientists reveal how patterns of brain activity direct specific body movements

July 20, 2017
New research by Columbia scientists offers fresh insight into how the brain tells the body to move, from simple behaviors like walking, to trained movements that may take years to master. The discovery in mice advances knowledge ...

Scientists discover combined sensory map for heat, humidity in fly brain

July 20, 2017
Northwestern University neuroscientists now can visualize how fruit flies sense and process humidity and temperature together through a "sensory map" within their brains, according to new research.

Team traces masculinization in mice to estrogen receptor in inhibitory neurons

July 20, 2017
Researchers at Cold Spring Harbor Laboratory (CSHL) have opened a black box in the brain whose contents explain one of the remarkable yet mysterious facts of life.

Speech language therapy delivered through the Internet leads to similar improvements as in-person treatment

July 20, 2017
Telerehabilitation helps healthcare professionals reach more patients in need, but some worry it doesn't offer the same quality of care as in-person treatment. This isn't the case, according to recent research by Baycrest.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.