New research explains why defects in the brain's white matter may be a key contributor to schizophrenia. The findings also demonstrate the mechanism of action of two genes already linked to the disease.
Prior studies associated the genes for neuregulin 1 (NRG1), a growth factor involved in brain development, and erbB4, a receptor on brain cells through which NRG1 exerts its action with schizophrenia. Until now, however, it hadn't been shown that alterations in these genes lead to psychiatric disorders, according to researchers at Children's Hospital Boston Neurobiology Program.
Working in a mouse model, this team demonstrated that alterations in NRG1-erbB signaling induce pathologic changes in the brain's white matter. They further show that these changes lead to alterations in biochemical signaling and to behaviors suggestive of mental illness.
The findings could also have implications for bipolar disorder, which has been linked with NRG1 and involves white matter defects, adds Gabriel Corfas, Ph.D., researcher at the Neurobiology.
The investigators blocked NRG1-erbB signaling in oligodendrocytes—the cells that form myelin, which insulates nerve fibers. These myelinated nerve fibers make up the brain's white matter. When NRG1-erbB signaling was blocked, the mice had more oligodendrocytes than normal mice. Additionally, these cells had fewer branches and formed a significantly thinner myelin sheath around nerve fibers. As a result, the nerve fibers conducted electrical impulses more slowly, the researchers found. The mice also had changes in the nerve cells that make and use dopamine.
Finally, mice whose NRG1-erbB signaling was blocked showed behavioral changes that appeared to be consistent with mental illness. They explored their environment less than normal mice and had reduced social interaction, thought to be a manifestation of negative schizophrenic symptoms. The mice also showed behaviors suggestive of anxiety and increased sensitivity to amphetamine.
The idea of schizophrenia arising from white-matter defects may also help explain the timing of its emergence, Dr. Corfas notes. Recent evidence suggests that myelination of the prefrontal cortex occurs not only during infancy and toddlerhood, but also during late adolescence or early adulthood—just when schizophrenia strikes.
The study will be published online by the Proceedings of the National Academy of Sciences.