Researchers at the University of Massachusetts Medical School and Baylor College of Medicine say that the findings might lead to better medications for the mental disorder.
In the study of human brain tissue, scientists found that schizophrenia may occur, partially, because of a problem in an intermittent on/off switch for a gene involved in making a key chemical messenger in the brain.
The researchers found that the gene is turned on at increasingly high rates during normal development of the prefrontal cortex, the part of the brain involved in higher functions like thinking and decision-making - but that this normal boost may not arise in people with schizophrenia.
The gene, GAD1, makes an enzyme necessary for production of the chemical messenger, called GABA. The more the gene is turned on, the more GABA synthesis can occur, under normal circumstances. Abnormalities in brain development and in GABA synthesis are known to play a role in schizophrenia, but the underlying molecular mechanisms are unknown.
In the study, scientists discovered that defects in specific epigenetic actions - biochemical reactions that regulate gene activity, such as turning genes on and off so that they can make substances like the GAD1 enzyme - are involved.
"This discovery opens a new area for exploration of schizophrenia. Studies have yielded very strong evidence that schizophrenia involves a decrease in the enzymes, like GAD1, that help make the neurotransmitter GABA. Now we're starting to identify the mechanisms involved, and our discoveries are pointing to potential new targets for medications," NIMH Director Thomas R. Insel, MD said.
Another clue that the scientist uncovered was an enzyme, called Mll1, that may play a role in the epigenetic actions. For genes to be turned on, temporary structural changes in certain proteins - histones - must take place to expose the genes' blueprints in DNA. The researchers found evidence that, in schizophrenia, changes in Mll1 activity may interfere with this process in histones whose alterations enable the GAD1 blueprint to be exposed.
The researchers also showed, in mice, that antipsychotic medications like clozapine appear to correct this epigenetic flaw. This raises the possibility of developing new medications aimed at correcting defects in the mechanisms involved, the authors said.
The researchers also found that people with three different variations of the GAD1 gene - variations previously associated with schizophrenia - also were more likely to have signs of a malfunction in brain development. Among them were indicators of altered epigenetic actions related to GABA synthesis.
"We've known that schizophrenia is a developmental disease, and that something happens in the maturation of the prefrontal cortex during this vulnerable period of life," Schahram Akbarian, co-researcher in the study, MD, PhD. University of Massachusetts Medical School, said.
"Now we're beginning to find out what it is, and that sets the stage for better ways of preventing and treating it," he added.
The study is published in the October 17 issue of the Journal of Neuroscience.