Department of Anesthesiology

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Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia.

TitleEvidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia.
Publication TypeJournal Article
Year of Publication2002
AuthorsAlbert KA, Hemmings HC, Adamo AIB, Potkin SG, Akbarian S, Sandman CA, Cotman CW, Bunney WE, Greengard P
JournalArch Gen Psychiatry
Volume59
Issue8
Pagination705-12
Date Published2002 Aug
ISSN0003-990X
KeywordsAdult, Aged, Alzheimer Disease, Antipsychotic Agents, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases, Dopamine and cAMP-Regulated Phosphoprotein 32, Female, Humans, Immunoblotting, Male, Middle Aged, Nerve Tissue Proteins, Phosphoproteins, Prefrontal Cortex, Schizophrenia, Synapsins
Abstract

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 alpha 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 alpha 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.

Alternate JournalArch. Gen. Psychiatry
PubMed ID12150646
Grant ListMH 40899 / MH / NIMH NIH HHS / United States
MH 44188 / MH / NIMH NIH HHS / United States
MH 60398 / MH / NIMH NIH HHS / United States
NS 01715 / NS / NINDS NIH HHS / United States
NS 21377 / NS / NINDS NIH HHS / United States