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When the researchers returned to their knockout mice, they found that animals lacking Hoxb8 carried 15 percent fewer microglia in their brains, suggesting that the cells are somehow necessary for normal neural wiring.
Capecchi and colleagues tested the idea by giving the mice bone marrow transplants. The brain harbors two kinds of microglia. About 60 percent of the cells are present in the brain from early in life. But the others descend from cells that originate in the bone marrow and then migrate into position. A bone marrow transplant can replace these cells.
When mice missing Hoxb8 received bone marrow from normal animals, most of them groomed less. Their fur filled in, and their skin sores healed. And when Capecchi and colleagues introduced bone marrow from mice lacking Hoxb8 into normal animals, the recipients began cleaning themselves excessively. The team reported its findings May 28, 2010, in Cell.
“People thought of microglia as scavengers,” Capecchi says. “But we say they are monitoring what’s going on in the brain and having an influence on the output.” In other words, they change behavior. The cells could modify how the brain works in several ways, he notes. They could release chemical messengers called cytokines that trigger brain cells to fire more or less often. Microglia also send out tendrils that cozy up to synapses, the junctions between nerve cells, and thus they might be able to alter the activity between neurons.
Capecchi and colleagues are extending the work to patients, testing people with trichotillomania to determine whether they carry defects in their Hoxb8 genes. He’d also like to study bone marrow recipients—around 300,000 of the procedures have been performed—to determine whether their behavior changed after the transplant.
Current OCD treatments include psychotherapy and drugs like Prozac (fluoxetine). But focusing on microglia could lead to alternatives that might work better than tricky therapies that try to fine-tune the nervous system, says Capecchi. “Treating the immune system, which we know more about, might have an influence on the disease.”