DARPP-32 May Be Culprit In Schizophrenia Symptoms

A team of researchers at Rockefeller University, Weill Cornell Medical College, and the University of California at Irvine have found that brain levels of the vital neuronal signal processor, DARPP-32, are significantly reduced in people with schizophrenia.

DARPP-32 has been the focus of intensified research in the past few years, as investigators have linked the function of the pivotal brain protein to the actions of dopamine, glutamate, and serotonin, as well as to the effects of antidepressant drugs, cocaine, opiates, and nicotine.

The latest report, in the August Archives of General Psychiatry, detailed work by lead author Katherine Albert, M.D., Ph.D., a professor of psychiatry, neurology, and neuroscience at Rockefeller University, and principal investigator Paul Greengard, Ph.D., a professor of neurosciences and director of the Laboratory of Molecular and Cellular Neuroscience at Rockefeller, along with Hugh Hemmings, M.D., Ph.D., professor of anesthesiology at Weill Cornell, and William Bunney Jr., M.D., the Della Martin professor of psychiatry at UC-Irvine. The work was funded through grants from the National Association for Research on Schizophrenia and Depression and the National Institutes of Health.

Greengard has been studying DARPP-32 for more than 20 years. He recently reported that DARPP-32 is the site of action for the SSRI fluoxetine (Psychiatric News, May 17). Greengard was awarded the 2000 Nobel Prize in physiology and medicine for his long-term contributions to research on neuronal signaling, including DARPP-32.

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

In the new report the researchers measured the amounts of DARPP-32 and two other significant neuronal proteins in postmortem samples from 14 subjects who had schizophrenia and from a control group matched for gender and age at death. The team also studied the levels of the three proteins in postmortem samples from a group of Alzheimer’s patients to control for any possible effect of neuroleptic medications that the patients with schizophrenia had taken.

Alzheimer’s disease is clinically and pathologically distinct from schizophrenia, yet patients with Alzheimer’s often are prescribed neuroleptic medications as their dementia advances.

DARPP-32 was found to be consistently and significantly reduced in the dorsolateral prefrontal cortex of the brains of patients who had schizophrenia, but not reduced in the brains of control patients or the patients who had Alzheimer’s disease. In addition, the other two intracellular proteins measured did not differ between the three groups of subjects.

The authors of the report concluded that “the observed abnormality in DARPP-32 in the dorsolateral prefrontal cortex could contribute to the compromised function of the cognitive-affective parallel circuit in patients with schizophrenia.” The lowered levels of DARPP-32, they noted, could be responsible for the “profound frontal cognitive deficits observed in patients with schizophrenia.”

The authors suggested that DARPP-32’s regulation of the neurotransmitters dopamine and glutamate—both implicated in the pathology of schizophrenia—and the lowered levels of DARPP-32 they found in the dorsolateral prefrontal cortex—an area of the brain pathologically associated with schizophrenia—strengthen the hypothesis.

“This study showed us that DARPP-32 is reduced in an area of the brain most often linked to schizophrenia,” said Hemmings. However, he cautioned, “it does not tell us that DARPP-32 causes this disease.” Further studies will need to be done, he said, to determine whether the lowered levels cause schizophrenia or whether schizophrenia leads to falling levels of the vital protein.

An abstract of “Evidence for Decreased DARPP-32 in the Prefrontal Cortex of Patients with Schizophrenia” is posted on the Web at http://archpsyc.ama-assn.org/issues/current/abs/yoa8132.html. ▪

Arch Gen Psychiatry 2002 59 705