Both Nature and Nurture Increase Risk for Schizophrenia
Researchers at Johns Hopkins University say they now have a better understanding of how both nature and nurture can affect a person’s risk for schizophrenia and abnormal brain development in general.
The team worked with genetically engineered mice, as well as the genomes of thousands of people with schizophrenia. They discovered that defects in schizophrenia-risk genes, together with environmental stress right after birth, can cause abnormal brain development and increase the risk of developing schizophrenia by nearly one and one-half times.
“Our study suggests that if people have a single genetic risk factor alone or a traumatic environment in very early childhood alone, they may not develop mental disorders like schizophrenia,” says Guo-li Ming, M.D., Ph.D., professor of neurology and member of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine.
“But the findings also suggest that someone who carries the genetic risk factor and experiences certain kinds of stress early in life may be more likely to develop the disease.”
Determining the exact cause or causes of schizophrenia has been notoriously difficult because of the interaction of multiple genes and environmental triggers, says Ming.
While searching for clues at the molecular level, the researchers honed in on the interaction of two factors long associated with the disease: Disrupted-in-Schizophrenia 1 (DISC1) protein, which is vital for brain development, and GABA, a brain chemical needed for normal brain function.
For the study, the researchers engineered mice to have lower levels of DISC1 protein in one type of neuron in the hippocampus—a region of the brain involved in learning, memory and mood regulation.
Through a microscope, they noted that newborn mouse brain cells with reduced levels of DISC1 protein had neurons similar in size and shape to those of mice with normal levels of DISC1 protein. The researchers then engineered the same neurons in mice to have more effective GABA. Those brain cells looked much different than regular neurons, with longer projections.
Newborn mice who were given both the more effective GABA and reduced levels of DISC1 had the longest projections, suggesting, Ming said, that abnormalities in both DISC1 and GABA together could alter developing neurons for the worse.
Meanwhile, other research teams at the University of Calgary and at the National Institute of Physiological Sciences in Japan were demonstrating in newborn mice that changes in environment and routine stress could keep GABA from working properly during development.
Next, the researchers studied both normal mice and those with reduced DISC1 levels in a stressful situation. To stress the mice, the newborns were separated from their mothers for three hours a day for ten days. The researchers then examined neurons from the stressed normal newborns and found no differences in their size, shape and organization compared with unstressed mice.
However, when they stressed newborn mice with reduced DISC1 levels, the neurons were larger, more disorganized and had more projections than the unstressed mouse neurons. In fact, the projections were going to the wrong parts of the brain.
Finally, to see if the results in mice held up to suspected human schizophrenia risk factors, the researchers compared the genetic sequences of 2,961 schizophrenia patients and healthy people from Scotland, Germany and the United States.
Results revealed that if a person’s genome featured one specific combination of single DNA letter changes, then that person is 1.4 times more likely than a person without it to develop schizophrenia. Risk did not increase, however, if there was a single DNA letter change in either one of these genes alone.
“Now that we have identified the precise genetic risks, we can rationally search for drugs that correct these defects,” says Hongjun Song, Ph.D., co-author, professor of neurology and director of the Stem Cell Program at the Institute for Cell Engineering.
The report is published in Cell.
Source: Johns Hopkins Medicine
Pedersen, T. (2012). Both Nature and Nurture Increase Risk for Schizophrenia. Psych Central. Retrieved on April 26, 2015, from http://psychcentral.com/news/2012/03/28/both-nature-and-nurture-increase-risk-for-schizophrenia/36615.html