Key to psychological disorder may lie in the immune system
Bone-marrow transplants cure obsessive-compulsive behaviour in mice.
A type of cell that is known to protect the brain against infection could be involved in a form of psychological disorder, a new study reveals. What's more, restoring normal populations of these cells by transplantation can cure abnormal behaviour in mice.
Microglia are highly branched immune cells that constantly move around and scavenge the brain for debris and pathogens. Researchers have now shown that a genetic defect that reduces the number of these cells causes excessive grooming in mice. The behaviour is similar to that observed in trichotillomania in humans — an obsessive-compulsive spectrum disorder that compels people to pull out their hair. "No connection had ever been made between microglia and behaviour," says Mario Capecchi at the University of Utah in Salt Lake City, whose team published the findings today in Cell1.
Scientists had presumed that abnormal behaviour stems from impaired neural function or brain development, says Christopher Pittenger, who studies the neural basis of psychiatric conditions at Yale University in New Haven, Connecticut. "To find that it has to do with microglia is a big surprise," says Pittenger, who was not involved in the new study.
Mutations in a gene that regulates the formation of blood cells causes mice to spend double the normal amount of time removing body hair, leading to bald spots and deep skin wounds2. The gene, called Hoxb8, comes from a family of genes that establish the body plan in the developing embryo and regulate the formation of organs and tissues.
Capecchi and his team found that Hoxb8 was expressed throughout the brain, but only in microglia. Moreover, animals with Hoxb8 mutations had fewer microglia than normal mice. The researchers pinpointed the origin of the microglia to bone marrow — soft tissue found in bone. The gene was expressed in bone-marrow stem cells, which produce many different types of blood cell, including one that may become microglia in the brain.
The researchers found that most of the animals with Hoxb8 mutations that received transplants of healthy bone marrow stopped their excessive grooming within four months. Their hair started to fill in the empty patches and their wounds began to heal. By contrast, a fraction of normal mice that received transplanted bone marrow from Hoxb8 mutant animals began to groom more than usual and developed hairless patches.
"It's a paradigm-shifting idea that you can transplant a compulsion into a normal animal," says Frank Burton, a neurobiologist at the University of Minnesota, Twin Cities.
Routine or worry?
Many psychiatric conditions have been associated with abnormal immune responses, but this study is unique because it shows a direct causal link, Capecchi says. He speculates that altered microglia may cause excessive grooming through their effects on neural activity. But the study has not ruled out a role for other immune cells or blood vessels.
It's also questionable whether the mouse model replicates features of obsessive-compulsive disorder in humans. The researchers haven't performed the key experiments to show that the behaviour is related to anxiety, says Francis Lee of Weill Cornell Medical College in New York City whose team last month reported a different mouse model of obsessive-compulsive behaviour3. Capecchi's team should also test whether drug treatments for obsessive-compulsive disorder alleviate symptoms in their mouse model, he says.
Although it's not clear how a dysfunction in the immune system causes neural circuits to go awry in psychiatric disorders, the scientists provide a valuable model for exploring these questions, Pittenger says. "I don't think these mice have obsessive-compulsive disorder, but I think they're fascinating and important and might ultimately shed some light on the disorder or other conditions," he says.
- Chen, S.-K. et al. Cell 141, 775-785 (2010).
- Greer, J. M. & Capecchi, M. R. Neuron 33, 23-34 (2002).
- Shmelkov, S. V. et al. Nature Med. 16, 598-602 (2010).