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

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.

• Authors: Katherine A Albert, Hugh C Hemmings Jr, Anna I B Adamo, Steven G Potkin, Schahram Akbarian, Curt A Sandman, Carl W Cotman, William E Bunney Jr, Paul Greengard
• Journal: Archives of general psychiatry (Arch Gen Psychiatry) Vol. 59 Issue 8 Pg. 705-12 (Aug 2002) ISSN: 0003-990X [Print] United States
• PMID: 12150646 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antipsychotic Agents
• Dopamine and cAMP-Regulated Phosphoprotein 32
• Nerve Tissue Proteins
• Phosphoproteins
• Synapsins
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Calcium-Calmodulin-Dependent Protein Kinases

Topics

• Adult
• Aged
• Alzheimer Disease (diagnosis, drug therapy, metabolism)
• Antipsychotic Agents (therapeutic use)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Calcium-Calmodulin-Dependent Protein Kinases (analysis, metabolism)
• Dopamine and cAMP-Regulated Phosphoprotein 32
• Female
• Humans
• Immunoblotting
• Male
• Middle Aged
• Nerve Tissue Proteins (analysis, metabolism)
• Phosphoproteins (analysis, metabolism)
• Prefrontal Cortex (chemistry, metabolism)
• Schizophrenia (diagnosis, drug therapy, metabolism)
• Synapsins (analysis, metabolism)