The mice shown here both had a mutant gene named Hoxb8 that originated in bone marrow and caused the mice to groom themselves pathologically, pulling out their hair. The mouse on the left displays hair loss on its chest and flank. After receiving a bone marrow transplant from a normal mouse three months earlier, the mouse at right fully recovered from the pathological grooming mutation and regrew its lost hair. University of Utah geneticist and Nobel Laureate Mario Capecchi says the study is the first to show and direct cause-and-effect link between an immune system defect and a psychiatric disorder. (Credit: Shau-Kwaun Chen, University of Utah)
Even more stunning, they report in the May 28th issue of Cell, the animals' neuropsychological behavior can be cured by bone marrow transplant.
It turns out that the Hoxb8 gene in question plays an important role in the development of immune cells known as microglia, which reside in the brain. Studies in which the researchers labeled Hoxb8 cells found that they show up in the brain exclusively in bone marrow-derived microglia. When they transplanted healthy bone marrow from control mice into the mutant animals, normal microglia made it to the animals' brains in about four weeks' time and many of the animals then stopped their incessant grooming, allowing their hair to grow back in, within three months of the procedure.
Those discoveries answered one big question "Why a Hox gene?" according to the researchers. After all, microglia arise from hematopoietic stem cells in bone marrow before they reach their final destination in the brain and Hox genes are known to be heavily involved in hematopoietic cells, according to Mario Capecchi of Howard Hughes Medical Institute and University of Utah School of Medicine.
"But then, microglia and behavior?" he asked. "We would expect neurons to control behavior -- the circuitry of the brain -- but then all of sudden we get this 'wild card' that microglia control behavior."
The classic job of microglia, which outnumber neurons in the brain, is to scan the brain for problems, he explained. When they find that something is wrong -- maybe a pathogen has invaded or there has been a stroke -- they change their shape to infiltrate the area and "clean up the mess." If you asked most any neuroscientist what microglia do, that's what they would probably tell you, Capecchi said.
In retrospect, he says, perhaps there were hints that microglia might be doing something more complicated. Fine processes that extend from the so-called resting microglia are always moving around in space. "They can cover the whole brain space every hour," he said. "The processes randomly 'walk' around extending and protracting, scanning the brain. They are quite dynamic even when they are called 'resting.'"
Others have recently shown that the cells move around and then suddenly stop at synapses (the connections between one neuron and the next). It appears that they stay at synapses that are active; otherwise, they simply wander away. "It says that for some reason they are monitoring neural activity," Capecchi said. "But why monitor it if you aren't going to do something about it?"
Capecchi now thinks based on the new findings connecting microglia to OCD-like behaviors in mice that the immune cells might not only monitor neural behavior but also modulate it, making sure it doesn't get out of hand. If they can't do their job properly, as in the Hoxb8 mutants, pathologies like the one they've seen in the mice may result.
Exactly how microglia might control brain activity is still anyone's guess, but the findings do add to evidence for a more general immune system role in mental disorders.
Capecchi notes that disorders such as depression, autism, Alzheimer's, and OCD do tend to be associated with immune deficiencies. But it wasn't really clear which came first. Genome-wide association studies in schizophrenia and OCD had also turned up genes involved in the immune system. But again, the connection wasn't entirely clear.
Capecchi said the new findings open the door to more detailed studies of how microglia and defects in microglia influence neural activity. They raise a host of other intriguing questions as well.
"Why couple behavior such as grooming to the host's immune system?" the researchers ask in conclusion. "From an evolutionary perspective it may make perfect sense to couple a behavior such as grooming, whose purpose is to reduce pathogen count, with the cellular machinery -- the innate and adaptive immune systems -- used to eliminate pathogens," they write.
"In summary," they continue, "we have provided strong support for the hypothesis that the excessive pathological grooming behavior exhibited by Hoxb8 mutant mice is caused by a defect in microglia. That a behavioral deficit could be corrected by bone marrow transplantation is indeed surprising. The therapeutic implications of our study on amelioration of neurological behavioral deficits in humans have not escaped us."
Capecchi said he wouldn't suggest a bone marrow transplant as a potential cure for mental disorders in humans today, given the significant risks associated with the procedure. But, as the saying goes, never say never.
Perhaps more importantly, he says, scientists still know a lot more about the immune system than they do about the brain. The new discovery suggests treatments "that improve the immune system may have benefits for the brain," he says. "It opens up the spectrum of possibilities you can think about."
The researchers include Shau-Kwaun Chen, Petr Tvrdik, Erik Peden, Scott Cho, Sen Wu, Gerald Spangrude, and Mario R. Capecchi, of the Howard Hughes Medical Institute, Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT.