Tying Together Genetic Associations -- MEDICA - World Forum for Medicine
Picture: Oligodendrocytes  
Oligodendrocytes from a normal
mouse (left) and a mutant
mouse (right); © Joshua Murtie

Prior genetic studies had linked schizophrenia to 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. But until now it hadn't been shown that alterations in these genes lead to psychiatric disorders, the researchers say.

Working in a mouse model they demonstrated that alterations in NRG1-erbB signalling induce pathologic changes in the brain's white matter. They further showed that these changes lead to alterations in biochemical signalling and to behaviours suggestive of mental illness. "We show that causing a defect in white matter is sufficient to cause biochemical and behavioural changes resembling those seen in neuropsychiatric disorders," says Gabriel Corfas, PhD Children's Hospital Boston, the study's senior author.

Working with mice, the researchers blocked NRG1-erbB signalling in oligodendrocytes –the cells that form the fatty sheath, known as myelin, which insulates nerve fibres. These myelinated nerve fibres make up the brain's white matter. When NRG1-erbB signalling was blocked, the mice had more oligodendrocytes than normal mice, but these cells had fewer branches and formed a significantly thinner myelin sheath around nerve fibres. As a result, the nerve fibres conducted electrical impulses more slowly, the researchers found.

The mice also had changes in the nerve cells that make and use dopamine, a key chemical in the brain that transmits messages from one nerve cell to another. "Changing the white matter in the brain apparently unbalanced the dopamine system, something that also occurs in patients with neuropsychiatric disorders," says Corfas. Finally, mice whose NRG1-erbB signalling was blocked showed behavioural changes that appeared to be consistent with mental illness.

"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," Corfas says.

MEDICA.de; Source: Children's Hospital Boston