Schizophrenia Is a Mystery, But This Discovery Might Change Things
Researchers Uncover New Cellular Pathway Behind Schizophrenia Risk
New study shows how a high-risk gene suppresses key brain chemical
By Lindsey Konkel
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February 23, 2019
Over the past few decades, researchers have identified more than 100 genes that may increase the risk of schizophrenia — a serious mental illness that can cause disordered thinking, delusions, and hallucinations. One of those genes is called neuregulin 3, and people with certain variations of this gene have an elevated risk of developing schizophrenia. But until recently, researchers weren’t sure exactly how neuregulin 3 influenced schizophrenia risk.
Study Reveals Clues to Causes of Schizophrenia and Other Serious Mental Illness
In a new study published online on February 20, 2019, in the journal Proceedings of the National Academy of Sciences, researchers at Case Western Reserve University in Cleveland showed that neuregulin 3 messes with certain neurotransmitters — chemicals that help brain cells communicate with each other. They say the findings could help one day in the development of more targeted drug treatments for schizophrenia and other serious mental illnesses.
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The Challenges of Schizophrenia Treatment
Schizophrenia affects about 1 in 100 people in the United States. The causes of schizophrenia aren’t well understood. Doctors and scientists think a combination of genetic and environmental factors likely play a role.
“The treatment of severe mental illness is far from satisfactory,” write the study authors. “The brain is so complex, and we are just starting to understand how different brain circuits and pathways interact to cause disease,” says Lin Mei, PhD, a neuroscientist at Case Western Reserve University School of Medicine in Cleveland, Ohio and senior study author.
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The new study helps shed light on one potential pathway: neuregulin 3 codes for a protein (also called neuregulin 3). Dr. Mei and colleagues knew that some people with schizophrenia have elevated levels of this protein, but it wasn’t clear what these elevated levels had to do with schizophrenia risk.
How This Study of Genetics and Serious Mental Illness Worked
Mei and colleagues mutated the gene encoding the neuregulin 3 protein in different groups of brain cells in mice. They wanted to show which types of brain cells might be sensitive to the changes in protein levels. When they mutated the gene in pyramidal neurons — a specialized type of brain cell that helps activate the brain — they found that the mice had difficulty navigating mazes and behaved strangely toward unfamiliar mice, behaviors that the researchers say are consistent with schizophrenia.
The mouse model is far from perfect, acknowledges Mei. Schizophrenia is a thought disorder, and it’s impossible to know what a mouse is thinking, he explains. “But we can try to model some of the symptoms,” he says. Mouse studies can help researchers to identify the types of nerve cells that might be involved, Mei adds.
RELATED: Mid-to-Late-Life Mental Illness: More Prevalent Than Previously Reported
Evidence Suggests Genes May Interfere With Brain Cell Communication
The researchers then took a closer look at how neuregulin 3 works on a cellular level. They grew pyramidal neurons in petri dishes in the lab, and increased the levels of neuregulin 3 to mimic the levels of the protein found in the brains of people with schizophrenia. They found that too much neuregulin 3 suppressed the release of a neurotransmitter called glutamate, which is found in the brain cells. It did so by messing with the formation of an important protein complex that helps usher neurotransmitters, such as glutamate, between nerve cells.
Glutamate is one of the main chemical messengers that brain cells use to communicate with each other. It helps to activate neurons and other brain cells and is important for learning and memory. Some people with schizophrenia have lower-than-normal levels of glutamate activity in the brain.
“Our study provides an explanation for how this glutamate hypofunction — or insufficiency — may occur in a subset of people with schizophrenia,” says Mei.
Uncovering New Drug Targets for Treating Schizophrenia
The molecular pathway by which the neuregulin 3 gene appears to control glutamate release is a new discovery. Uncovering novel pathways is an important first step in identifying new targets for drug therapy, according to Mei.
More research to help scientists understand how neuregulin 3 and other genes act to suppress neurotransmitter activity in the brain could lead to new therapy targets for a number of serious mental illnesses, he adds. In the future, for instance, a new medication could be designed to act on the neuregulin 3 gene and lower neuregulin 3 protein levels in the brains of people with schizophrenia.
More Research on Causes and Treatments of Schizophrenia Is Needed
Mei is quick to point out that such treatments are still a long way off. Gene therapies are unproven for the treatment of serious mental illness. In the case of neuregulin 3, it’s not yet known whether modulating the neuregulin 3 pathway to increase glutamate activity in the brain would actually lessen schizophrenia symptoms in people with the disorder. But, says Mei, it’s a start.
Video: The molecular logic of synapse formation in the brain
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