Gene Alterations Could Mean New Treatments for Schizophrenia

While studies have shown that several psychiatric disorders are associated with white matter defects, a new study suggests that those defects can cause alterations in dopaminergic function and behavior relevant to neuropsychiatric diseases.

The findings, published in the May 8 Proceedings of the National Academy of Sciences, may provide insight into new treatment options for patients with schizophrenia and bipolar disorder.

Using a mouse model, researchers led by Gabriel Corfas, PhD, Kristine Roy, PhD, and Joshua Murtie, PhD, of the Neurobiology Program at the Children’s Hospital in Boston, found that when Neuregulin 1 (NRG1), a growth factor, and erbB4, one of its receptors, are altered, it causes pathologic changes in the brain’s white matter. These changes also lead to alterations in biochemical signaling.

The researchers blocked NRG1-erbB signaling in oligodendrocytes in the mice. While this led to a proliferation of oligodendrocytes, the cells had fewer branches and formed a significantly thinner myelin sheath around nerve fibers, causing those fibers to conduct electrical impulses more slowly. The researchers also reported increased levels of functional dopamine receptors and transporters in the mice.

In addition, the mice whose NRG1-erbB signaling was blocked exhibited behavioral changes that appeared to be consistent with mental illness, including a lack of interest in their surroundings and social withdrawal—qualities thought to be a manifestation of “negative” schizophrenic symptoms. When exploring an open field, the transgenic mice were hypoactive, moving less quickly and stopping more often when compared to normal mice. And when the mice were subjected to a social interaction test in which an unfamiliar intruder male mouse was placed in the cages of both the transgenic and the normal mice, the transgenic mice were slower to investigate the intruder, compared to the normal mice. The transgenic mice also showed behaviors suggestive of anxiety, which is commonly seen in patients with schizophrenia and bipolar disorder, and an increased sensitivity to amphetamine, which is seen in many patients with schizophrenia.

The researchers said further investigation should be conducted on the possibility of modifying NRG1-erbB signaling with drugs as a way of treating or preventing schizophrenia.

“We need to investigate whether the white matter defects emerge early, before psychotic symptoms are evident,” said Dr. Corfas. “If they do, that raises the possibility of early diagnosis and preventive treatment.”

The idea of schizophrenia arising from white matter defects may also help explain the timing of emergence. Recent evidence suggests that myelination of the prefrontal cortex occurs not only during infancy and childhood but also during late adolescence or early adulthood, when schizophrenia strikes.

“We now need to go back to patients with schizophrenia and see whether those with variants of the NRG1 and erbB4 genes have differences in their white matter,” said Dr. Corfas. “It may be that there are different kinds of schizophrenia, arising from alterations in the different genes, and that directed treatments could be developed from different forms.”

The researchers plan to investigate other genes linked with schizophrenia, studying whether they interact with NRG1-erbB signaling and how they may alter brain function.                                                         

Suggested Reading
Roy K, Murtie JC, El-Khodor BF, et al. Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. Proc Natl Acad Sci U S A. 2007; ­104:­8131-8136.

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