Two new studies bolster the emerging idea that microglia, cells that were long dismissed as passive soldiers of the brain’s immune system, are in fact actively involved in shoring up connections between neurons. The unpublished work was presented Sunday at the 2013 Society for Neuroscience annual meeting in San Diego.
Microglia’s influence on the young brain is intriguing because several studies have linked the cells to autism and other neurodevelopmental disorders. One of the new studies suggests that microglia may be key to understanding the reported link between autism and prenatal exposure to antidepressants.
Microglia are shape-shifters. In their ‘resting state’ they look like spiders, with spindly projections reaching out to survey nearby cells. But in the presence of a pathogen, the cells retract their many branches and turn into amorphous blobs, capable of engulfing the pathogen and clearing away cellular garbage.
These so-called ‘activated microglia’ trigger brain inflammation and are hallmarks of many neurodegenerative diseases such as Alzheimer’s. Postmortem brains from individuals with autism also show elevated levels of activated microglia. Earlier this year, a brain imaging study found that men with autism carry an abundance of activated microglia in the cerebellum, a region involved in processing sensory information, movement and learning.
But other work over the past couple of years has hinted that microglia are also important for brain development. Resting microglia release growth factors that help other cells develop. They’re also crucial for the pruning of synapses, the junctions between neurons.
The second new study adds to this list of beneficial functions. It found that in newborn rats, microglia are required for the healthy production of myelin, the fatty substance that insulates neuronal branches and facilitates smooth transmission of electrical signals.
“This is a pretty big deal,” says Raymond Grill, assistant professor of integrative biology and pharmacology at the University of Texas Health Science Center at Houston, who was not involved in either new study.
For many years, Grill says, microglia were thought to be the scavengers of the brain, and nothing more. “If something goes wrong, they leap into effect to either protect or kill,” he says. “What this [research] is showing is that in early development, things are more complicated than that. Microglia are playing a very important role from Day One.”
Both new studies were led by Rick Lin, professor of neurobiology at the University of Mississippi Medical Center in Jackson. Lin stumbled across microglia in the course of his research on antidepressants.
A 2011 study found an association between taking antidepressants while pregnant and having a child with autism. A few months later, Lin’s team published results showing that pregnant rats exposed to a large dose of the antidepressant citalopram, widely marketed as Celexa, give birth to pups with severe social defects and abnormal long-range connections in their brains1.
“It really surprised us — the whole brain network of the exposed pups was totally messed up,” Lin says. “So then we started looking a little bit deeper.”
That study had also found that the exposed animals have abnormal levels of myelination — sometimes too much, sometimes too little. Because the cells that make up myelin, known as oligodendrocytes, are known to interact with microglia, the researchers looked at microglia in their rat model.
In unpublished work presented Sunday, they found that rat pups exposed to citalopram shortly after birth show an abundance of activated microglia in adulthood. The researchers don’t yet know whether the microglia are contributing to the brain abnormalities caused by the drug exposure or are trying to repair the damage.
“Microglia can be good policemen or bad policemen — anti-inflammatory or pro-inflammatory,” Lin says. Figuring out when they are harmful and when they’re helpful “is still the big question.”
This fits with another study presented at the conference by Lin’s collaborator, Yi Pang. His team injected the brains of live 4-day-old rats with a drug called clodronate, which dramatically depletes microglia but has no effect on neurons.
Animals with depleted microglia show significantly impaired myelination 21 days after birth, the study found.
The researchers propose that during development, microglia secrete growth factors that support myelin, allowing for smooth and fast connections in the brain. Impaired microglia could disrupt this process, leading to a wide range of problems, including autism.
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1. Simpson K.L. et al. Proc. Natl. Acad. Sci. U. S. A. 108, 18465-18470 (2011) PubMed