Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia

A mechanism for antipsychotic drug action?

Subroto Ghose, Kelly A. Gleason, Bryan W. Potts, Kelly Lewis-Amezcua, Carol A. Tamminga

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)812-820
Number of pages9
JournalAmerican Journal of Psychiatry
Volume166
Issue number7
DOIs
StatePublished - Jul 2009

Fingerprint

Glutamate Carboxypeptidase II
Antipsychotic Agents
Schizophrenia
Prefrontal Cortex
Proteins
Rodentia
Brain
metabotropic glutamate receptor 2
metabotropic glutamate receptor 3
Phase II Clinical Trials
Metabotropic Glutamate Receptors
Motor Cortex
Temporal Lobe
Antibodies
Enzymes

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia : A mechanism for antipsychotic drug action? / Ghose, Subroto; Gleason, Kelly A.; Potts, Bryan W.; Lewis-Amezcua, Kelly; Tamminga, Carol A.

In: American Journal of Psychiatry, Vol. 166, No. 7, 07.2009, p. 812-820.

Research output: Contribution to journalArticle

@article{de25a0ba73174236992a32e8254eb28f,
title = "Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia: A mechanism for antipsychotic drug action?",
abstract = "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.",
author = "Subroto Ghose and Gleason, {Kelly A.} and Potts, {Bryan W.} and Kelly Lewis-Amezcua and Tamminga, {Carol A.}",
year = "2009",
month = "7",
doi = "10.1176/appi.ajp.2009.08091445",
language = "English (US)",
volume = "166",
pages = "812--820",
journal = "American Journal of Psychiatry",
issn = "0002-953X",
publisher = "American Psychiatric Association",
number = "7",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=67649981850&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67649981850&partnerID=8YFLogxK

U2 - 10.1176/appi.ajp.2009.08091445

DO - 10.1176/appi.ajp.2009.08091445

M3 - Article

VL - 166

SP - 812

EP - 820

JO - American Journal of Psychiatry

JF - American Journal of Psychiatry

SN - 0002-953X

IS - 7

ER -