Pivotal Brain Processor Decreased in Schizophrenia

Lower Levels Could Explain Disruption in Mental Function<br />Study Points Toward Better Treatments

Aug 13, 2002


Levels of a pivotal signal processor in the brain are reduced significantly in people with schizophrenia, a study by scientists at Weill Cornell Medical College, The Rockefeller University, and University of California at Irvine (UCI) has found.

The findings suggest that the processor, which helps regulate key neurotransmitters in an area of the brain linked to schizophrenia, could eventually play a key role in reversing the brain dysfunctions associated with the disease. The study appears in the August issue of Archives of General Psychiatry.

Dr. Hugh Hemmings, professor of anesthesiology at Weill Cornell Medical College; Dr. Paul Greengard, professor of neuroscience at The Rockefeller University; and Dr. William Bunney, the Della Martin professor of psychiatry at UCI; and their colleagues found the processor, a chemical called DARPP-32, was reduced in the brains of deceased victims of schizophrenia.

DARPP-32 is the subject of increasing scientific scrutiny. The neurotransmitters dopamine, glutamate, and serotonin; the antidepressant Prozac; and even drugs of abuse like cocaine, opiates, and nicotine all have been found to work on the brain through the actions of DARPP-32. The molecule is suspected of integrating information throughout the brain and providing a blueprint for physiological activity. Dr. Greengard won the Nobel Prize for Medicine in 2000 for his work on DARPP-32.

"DARPP-32 is a key regulatory protein, involved in controlling receptors, ion channels, and other physiological factors, and is activated and de-activated ultimately by neurotransmitters that are implicated in the development of schizophrenia," Dr. Greengard said. "A reduction of DARPP-32 required for functions in the brain could contribute to the cognitive dysfunction seen in the disease."

The researchers studied the brains of 14 deceased people who had schizophrenia before they died. DARPP-32 was found to be reduced significantly in an area of the brain called the dorsolateral prefrontal cortex, which has consistently been associated with the symptoms of schizophrenia. The researchers found low levels of DARPP-32 in people who had had schizophrenia, but normal levels in people who did not have the disease. DARPP-32 was not found to be reduced in another area of the brain also associated with schizophrenia.

"This is the first study to show reduced levels of this important regulatory molecule in schizophrenia," said Dr. Bunney. "If DARPP-32 plays such a key role in controlling physiological activity in this part of the brain, perhaps there could be methods we could use to eventually maintain normal levels of the molecule."

The DARPP-32 molecule is known to control the actions of two neurotransmitters linked to schizophrenia—dopamine and glutamate. Schizophrenia affects about two million people in the United States; its cause is unknown. The dysfunctions in schizophrenia often result in severe social problems, delusions, hallucinations, reduced emotional responses, and grossly disorganized behavior, according to the National Association for Research on Schizophrenia and Depression.

"This study showed us that DARPP-32 is reduced in an area of the brain most often linked to schizophrenia," Dr. Hemmings said. "But it does not tell us that DARPP-32 causes this disease. We need to study whether it is a cause or another adaptation of the existing disease, and gain a more detailed understanding of its regulatory effects in the brains of schizophrenic patients and of people without the disease."

The researchers' work was supported by a number of gifts and grants, including those from the National Association for Research on Schizophrenia and Depression and the National Institutes of Health.

The researchers' colleagues in the study included Katherine Albert and Anna Adamo of Weill Cornell, and Steven Potkin, Schahram Akbarian, Curt Sandman, and Carl Cotman of UCI.