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Flawed Gene Activity May Contribute to Schizophrenia

By studying human brains from before birth through adulthood, researchers have identified a gene that increases its activity during normal brain development but that may fail to ramp up in people with schizophrenia. The faulty activity of this gene, called GAD1, may be to blame for at least some cases of schizophrenia, the scientists say.

In recent years, many researchers have begun to focus less on genes and more on other factors, called epigenetic factors, that affect gene activity without altering the DNA sequence itself. Epigenetic factors can turn genes on or off, affecting how much protein is made from a gene. Several human disorders, including cancer and psychiatric diseases, are known to be influenced by epigenetics.

In a new study published in the October 17, 2007, issue of the Journal of Neuroscience, Dr. Schahram Akbarian of the University of Massachusetts Medical School and his colleagues focused on the prefrontal cortex, a brain region known to malfunction in schizophrenia. This area is normally involved in higher functions like thinking and decision-making. The work was funded by NIH's National Institute of Mental Health (NIMH) and National Institute of Child Health and Human Development (NICHD).

The scientists looked first at postmortem brain tissue samples collected from prenatal and newborn infants, children and adults of varying ages. They found that, during prefrontal cortex development, the activity of the GAD1 gene increased steadily from before birth through puberty. GAD1 codes for an enzyme needed to produce the molecule GABA, a major neurotransmitter in the brain. Abnormal GABA production and brain development are known to play key roles in schizophrenia.

In healthy adult brains, the activity of GAD1 eventually leveled off or dropped slightly into older ages. In contrast, GAD1 activity appeared to be significantly reduced in brain samples from women with schizophrenia.

The control of GAD1 activity, the researchers found, lay in a part of the gene called its promoter. The promoter was being modified with a small chemical called a methyl group. Similar modifications were seen in other genes involved in GABA production.

The scientists found that the methylation was controlled by another enzyme called MLL1. When the researchers gave an antipsychotic medication to mice, it altered MLL1 activity and corrected the epigenetic flaw. This result raises the possibility of developing new medications to correct epigenetic defects.

"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. Now we're beginning to find out what it is, and that sets the stage for better ways of preventing and treating it," says Akbarian.