Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia: a mechanism for antipsychotic drug action?
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.


METHODS
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.
Ghose
Subroto
S
University of Texas Southwestern Medical Center, NE5.110C, Dallas, TX 75390-9127, USA. subroto.ghose@utsouthwestern.edu
Gleason
Kelly A
KA
Potts
Bryan W
BW
Lewis-Amezcua
Kelly
K
Tamminga
Carol A
CA
D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006220:Haloperidol / Q000627:therapeutic use; D006801:Humans; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000276:immunology / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
D014150:Antipsychotic Agents; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D006220:Haloperidol