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 has demonstrated the antipsychotic efficacy of a mGluR2/3 agonist. The current study was designed to distinguish the expression of mGluR2 and mGluR3 receptor protein in schizophrenia and to quantify glutamate carboxypeptidase II (GCPII) in order to explore a role for the metabotropic receptors in schizophrenia therapeutics. GCPII is an enzyme that metabolizes Nacetylaspartylglutamate (NAAG), the only known specific endogenous agonist of mGluR3 in the mammalian brain.Method-The normal expression levels of mGluR2, mGluR3 and GCPII were determined in 10 regions of the human post mortem brain using specific antibodies. Differences in expression levels of each protein were then examined in the dorsolateral prefrontal (DLPFC), temporal (TC) and motor cortex (MC) in 15 matched cases of schizophrenia and normal controls. Chronic antipsychotic treatment in rodents was conducted to examine the potential effect of antipsychotic drugs on expression of the 3 proteins.Results-We found a significant increase in GCPII protein and a reduction in mGluR3 protein in the DLPFC in schizophrenia with mGluR2 protein levels unchanged. Chronic antipsychotic treatment in rodents did not influence GCPII or mGluR3 levels.Conclusions-Increased GCPII expression and low mGluR3 expression in the DLPFC 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 mGluR2/3 agonists.

mGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions

“…1,2 Although initial trials with mGluR2/3 agonists have had mixed results, [3][4][5][6][7] data increasingly indicate that changes in mGluR3 are associated with schizophrenia and aging, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] encouraging this treatment strategy. Clinical trials were originally based on data from rodent models.…”

“…45,46 Insults to disrupted in schizophrenia 1 and phosphodiesterase 4A are linked to increased risk of illness. 47,48 Importantly, genetic alterations in mGluR3 are increasingly linked to schizophrenia, [8][9][10][11][12][13][14][15][16][17][18][19][20][21] including altered dlPFC activation and poorer cognitive performance. 9,11 In particular, there is reduced mGluR3 protein in schizophrenia dlPFC, and an increase in GCPII, the enzyme that catabolizes the endogenous mGluR3 ligand, NAAG.…”

Effect of metabotropic glutamate receptor-3 variants on prefrontal brain activity in schizophrenia: An imaging genetics study using multi-channel near-infrared spectroscopy

“…Of these, GRM3 is differentially distributed among the presynaptic, postsynaptic, and glial compartments, and it has effects on the modulation of NMDA receptor function and local microcirculation (Ghose et al, 2009). The GRM3 agonist LY354740 could improve anxiety symptoms (Dunayevich et al, 2007;Michelson et al, 2005) and cognitive impairment (Krystal et al, 2005).…”

The mGluR2/3 agonist LY379268 reverses post-weaning social isolation-induced recognition memory deficits in the rat

“…They are predominantly (but not exclusively) localised in the extra-synaptic area of presynaptic neurones and are most abundant in brain regions associated with psychiatric disease, such as the hippocampus, striatum, neocortex and amygdala (Cartmell and Schoepp 2000;Imre et al 2006). Post-mortem studies on tissue from both medicated and un-medicated schizophrenic patients show changes in mGluR2/3 protein and/or gene expression in several areas of the prefrontal cortex (PFC) (Ghose et al 2008;Ghose et al 2009;Gupta et al 2005), a region implicated in cognitive dysfunction. Furthermore, activation of these presynaptic autoreceptors directly augments glutamate release from synaptic terminals in some neurones (Cartmell and Schoepp 2000).…”