Neurons have always taken the starring role in research on brain function and disease, but recently members of the brain’s supporting cast, oligodendrocytes, have been getting their due. A study in the lab of Gabriel Corfas, HMS associate professor of neurology and otolaryngology at Children’s Hospital Boston, provides evidence that defects in oligodendrocytes, the cells that make up the brain’s white matter, can cause neural and behavioral changes in mice suggestive of psychiatric disease.
Irregularities have been seen in the white matter of patients with neuropsychiatric diseases like schizophrenia, but it has not been clear whether they are causes or consequences of disease. At the same time, studies have linked genetic changes in the growth factor neuregulin-1 (NRG1) and one of its receptors, erbB4, to schizophrenia and bipolar disorder, but how these changes affect the brain is unknown. Corfas’s team, led by research fellows Kristine Roy and Joshua Murtie, created transgenic mice in which this signaling pathway is blocked in just the brain’s oligodendrocytes.
Examining the brains of the transgenic mice, the team discovered subtle changes in the oligodendrocytes, which send out branches that attach to nerve cell axons, wrapping them in insulating sheaths of myelin. The mice had more oligodendrocytes, but the cells were simpler, with fewer branches and thinner myelin sheaths.
The transgenic mice also behaved differently. When placed in a box, they moved and explored less, and their activity further decreased after repeated exposures. They lingered near the walls, a behavior suggestive of anxiety. Their social interaction was also different; when faced with an intruder mouse, the transgenic mice responded more slowly and took longer to investigate the intruder with repeated exposures. The study, which appeared in the May 8 Proceedings of the National Academy of Sciences, shows that “it’s enough to change white matter in very subtle ways to have a dramatic effect on behavior,” Corfas said.
The transgenic mice also became increasingly hyperactive in response to amphetamine, a sign of defects in the dopamine pathway. The team found a higher level of dopamine receptors and transporters in the neurons of the transgenic mice. The alterations in behavior and dopamine signaling suggest that white matter changes could be a cause rather than a byproduct of neuropsychiatric disease.
Corfas notes that in addition to the genetic alterations known to occur in the neuregulin pathway, environmental insults could also affect it. The next steps, he said, are to clarify how changes in the brain’s white matter could affect how neurons use dopamine and to start looking for evidence in humans of a relationship between neuregulin-1 signaling, white matter defects, and psychiatric disease.
