UC Davis researchers probe microglia’s role in developing brain

Microglia remove not only foreign bodies, dying cells and pathogens in the brain but also healthy neural progenitor cells through phagocytosis to control neuron production during brain development, a discovery that could present new avenues for brain research and possibly lead to the development of new therapies

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SACRAMENTO, Calif.—A study recently published by researchersat the University of California Davis MIND Institute has found that microglia,macrophages that remove foreign bodies, dying cells and pathogens in the brain,also remove healthy neural progenitor cells (NPCs) through phagocytosis tocontrol neuron production during brain development. According to theresearchers, their discovery could present new avenues for brain research andpossibly lead to the development of new therapies to treat a variety ofneurological conditions.
The study, "Microglia Regulate the Number of NeuralPrecursor Cells in the Developing Cerebral Cortex," was published Feb. 26 inthe online version of The Journal ofNeuroscience.
Microglia are constantly "scavenging" the central nervoussystem for plaques, damaged neurons and infectious agents. In the case whereinfectious agents are directly introduced to the brain or cross the blood-brainbarrier, microglial cells must react quickly to decrease inflammation anddestroy the infectious agents before they damage the sensitive neural tissue.
Microglial cells colonize the cerebral cortex duringprenatal development and comprise 5 to 6 percent of all cortical cells. Yet,despite recent progress elucidating the function of microglia in the developingcentral nervous system and a wealth of knowledge on microglial function in themature brain, the functional roles of microglia during prenatal cortical developmentare not well understood.
"In my lab, we study the developing brain," says Dr. StephenNoctor, assistant professor in the Department of Psychiatry and BehavioralSciences and the study's lead author. "In the adult brain, there is a hugedatabase on what cells do. What we studied is role of microglia in theembryonic brain."
To do so, the researchers studied brain tissue from primatesand rats, observing that microglia colonize the proliferative zones of theprenatal brain. The researchers labeled the microglia and NPCs with antibodiesand other markers to track microglial status and their interactions withprogenitor cells. The researchers noted that microglia were concentrated in theproliferative zone where NPCs proliferate and produce new neurons.
They further observed that 95 percent of microglia in theproliferative zone were activated. Even more importantly, they were engulfingand eating NPCs. However, the team had to determine the NPC's health status. Ifthe NPCs were dead or dying, the microglial activity would not have beenunusual, as removing these cells is one of their primary functions.
The investigators found that PS-expressing cells could befound throughout the brain, but were not concentrated with microglia in theproliferative zones. Other experiments indicated that the NPCs being targetedby microglia were healthy cells. In addition, regional differences in thedistribution of microglia point to another role for the cells. By selectivelyeliminating NPCs, and as a result neurons, they may contribute to thedevelopment of regional differences in brain architecture, the researchersfound.
"We show here that microglia colonize the neuralproliferative zones in the developing neocortex of rodents, monkeys and humanand phagocytose neural precursor cells, particularly during late stages ofcortical neurogenesis," the research team wrote in its paper. "We demonstratethat the vast majority of microglia in the developing prenatal and postnatalcerebral cortex has an activated morphology and express markers associated withactivation. We also show that augmenting in-uteroactivation of fetal microglia through maternal immune activation decreases thenumber of neural precursor cells, and that in-uterodeactivation or elimination of fetal microglia increase the number ofneural precursor cells in the developing cerebral cortex. Together, these datademonstrate that microglia play a key role in cortical development under normaland pathological conditions."
"What we investigated in this paper is whether you can alteractivity in these cells," Noctor sums up. "This has an impact on the number ofneural stem cells in the brain. There could be a connection to schizophrenia,as in some cases, papers have reported that mothers of schizophrenic childrenwho have infections produce an immune response for that. The mother's immuneresponse can cross into the baby's brain, and this may further activate fetalmicroglia, which chew up more than they should.
"Autism may also be correlated with this immune response,"Noctor adds. "In one way or another, they may be overeating or deactivatingthese neural cells that play a role in the pathology."
There are drugs on the market that deactivate microglia,Noctor notes.
"We could potentially use these tools to control microglialactivation in controlled studies to determine if this is a viable way torestore the brain's proper balance," he says.
Other researchers who worked on the paper were ChristopherCunningham of UC Davis and Verónica Martínez-Cerdeño of UC Davis and Shriner'sHospitals for Children-Northern California. Funding for the study was providedby the MIND Institute, the Children's Miracle Network, the National ScienceFoundation and a U.S. National Institutes of Health grant.

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