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UC Davis researchers probe microglia’s role in developing brain
SACRAMENTO, Calif.—A study recently published by researchers at 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 to control neuron production during brain development. According to the researchers, their discovery could present new avenues for brain research and possibly lead to the development of new therapies to treat a variety of neurological conditions.
The study, "Microglia Regulate the Number of Neural Precursor Cells in the Developing Cerebral Cortex," was published Feb. 26 in the online version of The Journal of Neuroscience.
Microglia are constantly "scavenging" the central nervous system for plaques, damaged neurons and infectious agents. In the case where infectious agents are directly introduced to the brain or cross the blood-brain barrier, microglial cells must react quickly to decrease inflammation and destroy the infectious agents before they damage the sensitive neural tissue.
Microglial cells colonize the cerebral cortex during prenatal development and comprise 5 to 6 percent of all cortical cells. Yet, despite recent progress elucidating the function of microglia in the developing central nervous system and a wealth of knowledge on microglial function in the mature brain, the functional roles of microglia during prenatal cortical development are not well understood.
"In my lab, we study the developing brain," says Dr. Stephen Noctor, assistant professor in the Department of Psychiatry and Behavioral Sciences and the study's lead author. "In the adult brain, there is a huge database on what cells do. What we studied is role of microglia in the embryonic brain."
To do so, the researchers studied brain tissue from primates and rats, observing 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 and their interactions with progenitor cells. The researchers noted that microglia were concentrated in the proliferative zone where NPCs proliferate and produce new neurons.
They further observed that 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.
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. 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, the researchers found.
"We show here that microglia colonize the neural proliferative zones in the developing neocortex of rodents, monkeys and human and phagocytose neural precursor cells, particularly during late stages of cortical neurogenesis," the research team wrote in its paper. "We demonstrate that the vast majority of microglia in the developing prenatal and postnatal cerebral cortex has an activated morphology and express markers associated with activation. We also show that augmenting in-utero activation of fetal microglia through maternal immune activation decreases the number of neural precursor cells, and that in-utero deactivation or elimination of fetal microglia increase the number of neural precursor cells in the developing cerebral cortex. Together, these data demonstrate that microglia play a key role in cortical development under normal and pathological conditions."
"What we investigated in this paper is whether you can alter activity in these cells," Noctor sums up. "This has an impact on the number of neural stem cells in the brain. There could be a connection to schizophrenia, as in some cases, papers have reported that mothers of schizophrenic children who have infections produce an immune response for that. The mother's immune response can cross into the baby's brain, and this may further activate fetal microglia, 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 deactivating these 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 microglial activation in controlled studies to determine if this is a viable way to restore the brain's proper balance," he says.
Other researchers who worked on the paper were Christopher Cunningham of UC Davis and Verónica Martínez-Cerdeño of UC Davis and Shriner's Hospitals for Children-Northern California. Funding for the study was provided by the MIND Institute, the Children's Miracle Network, the National Science Foundation and a U.S. National Institutes of Health grant.