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.

Fig. 1

Bar graphs showing levels of mGluR2 and mGluR3 in 10 brain regions (PFC = dorsolateral prefrontal cortex, ACC = anterior cingulate, OFC = orbitofrontal cortex, PC = parietal cortex, CN = caudate nucleus, NAc = nucleus accumbens, TH = thalamus, HC = hippocampus, CB = cerebellum, OCC = occipital cortex). Grey bars represent mGluR2 protein levels, black bars represent mGluR3 protein. Data shown are mean ± standard error.

Fig. 2

Post mortem human tissue samples from 15 pairs of matched controls (CON) and cases of schizophrenia (SCH) were analyzed by immunoblotting to detect GCPII, mGluR2 and mGluR3 protein levels relative to β tubulin (loading control) in the prefrontal cortex (PFC), temporal cortex (TC) and motor cortex (MC) in cases. Data shown for GCP II and mGluR3 are mean ± S.D. Asterisk (*) denotes significant difference between diagnostic groups (p < 0.05)

Fig. 3

Graphs showing absence of an effect of chronic treatment in rodents (n = 10 each group) with haloperidol (1.5 mg/kg/day; hatched bars) or risperidone (6 mg/kg/day; filled bars) compared to water on GCP II and mGluR3 protein expression in the frontal cortex. Data shown are mean ± S.D.

Fig. 4

Schematic representation of the 3 compartments of the normal synapse (pre-synaptic, post synaptic terminals and glial cell) with localization of mGluR3 and GCP II (A). NAAG is released from the pre-synaptic terminal into the synapse (1) where it can activate mGluR3 receptors located at (a) the postsynaptic terminal to potentiate NMDA responses (+) and regulate GABA-A receptor subunit expression, (b) presynaptic terminal to regulate its own release (−) or (c) glial cell where it mediates the release of TGFβ and modulates local microcirculation. In schizophrenia (B), high GCPII and low mGluR3 impair NAAG-mediated activation at the mGluR3 receptor. This could reduce NMDA potentiation, alter GABA-A receptor composition, release NAAG which is metabolized by higher GCPII levels, decrease TGFβ release and reduce regional blood flow. (C) mGluR2/3 agonists could reverse the effects of high GCPII and low mGluR3 be restoring function at the mGluR3 receptor.