Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia.
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.
Albert
Katherine A
KA
Laboratory of Molecular and Cellular Neuroscience, the Rockefeller University, New York, NY, USA.
Hemmings
Hugh C
HC
Adamo
Anna I B
AI
Potkin
Steven G
SG
Akbarian
Schahram
S
Sandman
Curt A
CA
Cotman
Carl W
CW
Bunney
William E
WE
Greengard
Paul
P
D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism; D014150:Antipsychotic Agents / Q000627:therapeutic use; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000032:analysis* / Q000378:metabolism; D010750:Phosphoproteins / Q000032:analysis* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000737:chemistry* / Q000378:metabolism; D012559:Schizophrenia / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D016704:Synapsins / Q000032:analysis / Q000378:metabolism
D014150:Antipsychotic Agents; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D016704:Synapsins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases