Genes linked to schizophrenia might function to cause the disease

Animal research at Wake Forest University Baptist Medical Center has found how one of the genes linked to schizophrenia might function to cause the disease. The work was reported today at the annual meeting of the Society for Neuroscience in San Diego.

"Our research in mice suggests that defects in a gene may interfere with communication between nerve cells in the brain," said Ashok Hegde, Ph.D. "We believe this may cause a common symptom of schizophrenia – being unable to filter out unimportant sensory information."

Schizophrenia tends to run in families and has been linked to several different genes. Hegde and colleagues studied RGS4, a gene that is believed to control the release of neurotransmitters, the molecules that help nerve cells communicate with each other. Recent studies in humans show that less of the protein produced by the RGS4 gene is found in the brains of patients with schizophrenia.

"Through our research on mouse brain nerve cell circuitry, we have shown that this gene can control communication between nerve cells in the brain," said Hegde, assistant professor of neurobiology and anatomy. "Our ultimate goal is to better understand the cause of schizophrenia and to help in developing more effective drug treatments."

Hegde and colleagues studied a part of the mouse brain that has two major types of nerve cells similar to the nerve cells that malfunction in people suffering from schizophrenia. One type of cell gets excited and sends signals to other nerve cells. The other type blocks such signals. The cells that block signals are important in controlling how much communication takes place between nerve cells.

In normal people, the signal-blocking nerve cells act as gatekeepers. They promote communication only if the information from outside is strong enough or relevant enough. Scientists believe that in schizophrenia patients, the signal-blocking cells are weak.

"The excited cells do not listen to the signal-blocking nerve cells and chatter whether the news from the outside world is important or not," said Hegde. "So, people with schizophrenia may respond to every little thing that hits their senses, such as slight noise in the background."

To test their hypothesis that RGS4 is involved in brain signaling, Hegde and colleagues injected the RGS4 protein in a nerve cell and measured "calcium current," a marker for the levels of neurotransmitters released by nerve cells. They found that the protein increased levels of neurotransmitter, suggesting that RGS4 helps nerve cells communicate better with each other.

Their study of nerve cell circuitry is a new approach to learning about schizophrenia.

"We believe this can tell us a lot about how defects in genes might cause schizophrenia," said Hegde. "Our next step will be to see if defects in RGS4 can actually cause schizophrenia-like symptoms."

They plan to study a simple behavior: the startle response to a loud noise. Normal people are startled when they hear a loud noise. On the other hand, if normal people first hear a not-so-loud noise followed by a loud noise, they are not startled as much as by the loud noise alone. In people with schizophrenia, the startle response is abnormal – they are startled by the loud noise even if they hear a not-so-loud noise first.

Mice and rats have responses similar to normal people. The researchers will study mice to see if a shortage of RGS4 causes an abnormal startle response and schizophrenia-like symptoms.

Schizophrenia is a devastating mental illness that affects about 2 million Americans in a year. Worldwide, 1 percent of the population suffers from schizophrenia. The most common symptoms of schizophrenia are delusions and hallucinations. People suffering from schizophrenia lose the ability to think properly and cannot tell what is important from unimportant information in their surroundings.