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Evidence for Decreased DARPP-32 in the Prefrontal Cortex of Patients With Schizophrenia
Katherine A. Albert, MD, PhD;
Hugh C. Hemmings, Jr, MD, PhD;
Anna I. B. Adamo, RT;
Steven G. Potkin, MD;
Schahram Akbarian, MD, PhD;
Curt A. Sandman, PhD;
Carl W. Cotman, PhD;
William E. Bunney, Jr, MD;
Paul Greengard, PhD
Arch Gen Psychiatry. 2002;59:705-712.
Background The neurotransmitters dopamine and glutamate have been implicated in
the prefrontal dysfunction associated with schizophrenic illness. Studies
suggest that the D1 subclass of dopamine receptor and the N-methyl-D-aspartate subclass of glutamate receptor are involved in
this prefrontal dysfunction. These 2 receptors regulate, in opposing directions,
the amount of phosphorylated activated DARPP-32, a potent inhibitor of protein
phosphatase 1 that modulates the activity of several classes of receptors
and ion channels. Thus, DARPP-32 occupies a key regulatory position, and may
play an important role in the pathophysiological changes in dopamine and glutamate
function reported in patients with schizophrenia.
Methods The amounts of DARPP-32, synapsin I, and the  subunit of calcium/calmodulin-dependent
protein kinase II were measured by immunoblotting in postmortem samples from
14 schizophrenic subjects and their age-, gender-, and autolysis time–matched
control subjects. Possible confounding influences of neuroleptic treatment
were analyzed by comparing subjects with Alzheimer disease who were and were
not treated with neuroleptic agents.
Results DARPP-32 was significantly reduced in the dorsolateral prefrontal cortex
in more schizophrenic subjects relative to matched controls. The ratios of
2 other synaptic phosphoproteins, synapsin I and the subunit of calcium/calmodulin-dependent
protein kinase II, did not differ between schizophrenic and control subjects,
nor between subjects with Alzheimer disease who were and were not treated
with neuroleptic agents.
Conclusions Our findings are consistent with a selective reduction in DARPP-32 levels
in schizophrenic subjects. This may be involved in the prefrontal dysfunction
associated with schizophrenia.
From the Laboratory of Molecular and Cellular Neuroscience, the Rockefeller
University (Drs Albert, Hemmings, and Greengard), the Departments of Psychiatry
(Dr Albert), Neurology and Neuroscience (Dr Albert), and Anesthesiology and
Pharmacology (Dr Hemmings and Ms Adamo), Weill Medical College of Cornell
University, New York, NY; and the Departments of Psychiatry and Human Behavior
(Drs Potkin, Akbarian, Sandman, and Bunney), Neurology (Dr Cotman), and Psychobiology
(Dr Cotman), University of California, Irvine. Dr Akbarian is now with the
Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School,
Boston.
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