TY - JOUR
T1 - Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia
T2 - A mechanism for antipsychotic drug action?
AU - Ghose, Subroto
AU - Gleason, Kelly A.
AU - Potts, Bryan W.
AU - Lewis-Amezcua, Kelly
AU - Tamminga, Carol A.
PY - 2009/7
Y1 - 2009/7
N2 - Objective: Preclinical and clinical data implicate the group II metabotropic glutamate receptors mGluR2 and mGluR3 in the pathophysiology of schizophrenia. Moreover, a recent phase II clinical trial demonstrated the antipsychotic efficacy of a mGluR2/mGluR3 agonist. The purpose of the present study was to distinguish the expression of mGluR2 and mGluR3 receptor proteins in schizophrenia and to quantify glutamate carboxypeptidase II (GCP II) in order to explore a role for the metabotropic receptors in schizophrenia therapeutics. GCP II is an enzyme that metabolizes N-acetyl-aspartyl-glutamate (NAAG), which is the only known specific endogenous agonist of mGluR3 in the mammalian brain. Method: The normal expression levels of mGluR2, mGluR3, and GCP II were determined for 10 regions of the postmortem human brain using specific antibodies. Differences in expression levels of each protein were examined in the dorsolateral prefrontal cortex, temporal cortex, and motor cortex in 15 postmortem schizophrenia subjects and 15 postmortem matched normal comparison subjects. Chronic antipsychotic treatment in rodents was conducted to examine the potential effect of antipsychotic drugs on expression of the three proteins. Results: Findings revealed a significant increase in GCP II protein and a reduction in mGluR3 protein in the dorsolateral prefrontal cortex in schizophrenia subjects, with mGluR2 protein levels unchanged. Chronic antipsychotic treatment in rodents did not influence GCP II or mGluR3 levels. Conclusions: Increased GCP II expression and low mGluR3 expression in the dorsolateral prefrontal cortex suggest that NAAG-mediated signaling is impaired in this brain region in schizophrenia. Further, these data implicate the mGluR3 receptor in the antipsychotic action of mGluR2/mGluR3 agonists.
AB - Objective: Preclinical and clinical data implicate the group II metabotropic glutamate receptors mGluR2 and mGluR3 in the pathophysiology of schizophrenia. Moreover, a recent phase II clinical trial demonstrated the antipsychotic efficacy of a mGluR2/mGluR3 agonist. The purpose of the present study was to distinguish the expression of mGluR2 and mGluR3 receptor proteins in schizophrenia and to quantify glutamate carboxypeptidase II (GCP II) in order to explore a role for the metabotropic receptors in schizophrenia therapeutics. GCP II is an enzyme that metabolizes N-acetyl-aspartyl-glutamate (NAAG), which is the only known specific endogenous agonist of mGluR3 in the mammalian brain. Method: The normal expression levels of mGluR2, mGluR3, and GCP II were determined for 10 regions of the postmortem human brain using specific antibodies. Differences in expression levels of each protein were examined in the dorsolateral prefrontal cortex, temporal cortex, and motor cortex in 15 postmortem schizophrenia subjects and 15 postmortem matched normal comparison subjects. Chronic antipsychotic treatment in rodents was conducted to examine the potential effect of antipsychotic drugs on expression of the three proteins. Results: Findings revealed a significant increase in GCP II protein and a reduction in mGluR3 protein in the dorsolateral prefrontal cortex in schizophrenia subjects, with mGluR2 protein levels unchanged. Chronic antipsychotic treatment in rodents did not influence GCP II or mGluR3 levels. Conclusions: Increased GCP II expression and low mGluR3 expression in the dorsolateral prefrontal cortex suggest that NAAG-mediated signaling is impaired in this brain region in schizophrenia. Further, these data implicate the mGluR3 receptor in the antipsychotic action of mGluR2/mGluR3 agonists.
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U2 - 10.1176/appi.ajp.2009.08091445
DO - 10.1176/appi.ajp.2009.08091445
M3 - Article
C2 - 19487395
AN - SCOPUS:67649981850
SN - 0002-953X
VL - 166
SP - 812
EP - 820
JO - American Journal of Psychiatry
JF - American Journal of Psychiatry
IS - 7
ER -