SLOW-GROWING: Oligodendrocytes in mice with compromised signaling of the growth factor neuregulin 1 (right) are smaller with fewer branches than normal cells. Image: IMAGE: JOSHUA MURTIE, PhD, CHILDREN'S HOSPITAL BOSTON
Scientists have suspected for more than two decades that schizophrenia is linked to defects in the brain's white matter. They could not tell, however, whether changes in the information-transmitting region of the brain detected by brain scans or autopsies were the cause or the symptoms of the illness.
A new study not only clarifies the association but also links it to genes previously tied to the debilitating mental disorder and chemical changes believed to occur in the schizophrenic brain. "[The report] provides evidence that alterations in myelin [the lipid layers that sheath and insulate nerve fibers and are the main constituent of white matter] can cause defects in neurons and the central nervous system in general that are related to neuropsychiatric disease," says the study's senior author Gabriel Corfas, a professor of neurology at Harvard Medical School's Children's Hospital Boston.
The findings, published in the Proceedings of the National Academy of Sciences USA, could help physicians detect schizophrenia earlier and lead to new treatments for sufferers. Schizophrenia, which affects about 2.5 million people in the U.S., is characterized by a distorted sense of reality, such as hallucinations and imaginary voices, erratic behavior and speech, and the absence of emotion. Symptoms do not typically show up until late adolescence or early adulthood.
Corfas's team studied mice in which they blocked the erbB4 receptor, in oligodendrocytes, which make up the myelin sheath over a neuron's communication hub. The erbB4 receptors receive a growth factor called neuregulin 1, which is necessary for proper brain development. Genes expressed in oligodendrocytes—such as the one that codes for neuregulin 1—have previously been linked to schizophrenia, bipolar disorder, depression and obsessive-compulsive disorder.
The team notes that when mice's erbB4 receptors are blocked, they develop up 40 percent more oligodendrocytes than normal specimens. "This is something we did not expect," Corfas says. "The perception in the field was that [neuregulin 1 function] was a survival factor of oligodendrocytes." In other words, researchers expected the defect to lead to fewer cells, not more.
Furthermore, oligodendrocytes are characterized by several branching points with successive branches coming off of them; scientists found that those produced by the altered mice developed fewer splitting points and branches, resulting in a thinner myelin layer coating their neurons. Researchers measured an 18 percent slower speed of information transmission in the brains with thinner myelin layers compared with normal ones. "The timing between different centers in the brain would be disrupted," Corfas says, likening it to a delay in information relayed during phone calls. Mice with disrupted erbB4 receptors also showed several behaviors that may correspond to asocial symptoms in humans: They were less likely to explore an open field, or to investigate an unknown intruder placed in their cage.
The mutant mice also proved to be more sensitive to amphetamines—a hallmark of schizophrenia in humans—becoming far more hyperactive than the control mice after taking repeated doses. This suggested there were changes to the system for the neurotransmitter dopamine associated with the brain's pleasure and reward mechanisms. Indeed, when the investigators followed this lead, they found that certain types of dopamine receptors had increased in quantity. (Most antipsychotics used to treat schizophrenia suppress dopamine.)
Corfas says that the new findings indicate that screening children with noticeable cognitive and social defects for increased white matter or changes in its organization could lead to earlier diagnosis of schizophrenia. In addition, he says the results indicate that therapies designed to treat other white matter disorders such as multiple sclerosis could be useful in treating schizophrenia and other neuropsychiatric disorders.