Effect of antipsychotic drugs on group II metabotropic glutamate receptor expression and epigenetic control in postmortem brains of schizophrenia subjects.

Antipsychotic-induced low availability of group II metabotropic glutamate receptors (including mGlu2 R and mGlu3 R) in brains of schizophrenia patients may explain the limited efficacy of mGlu2/3 R ligands in clinical trials. Studies evaluating mGlu2/3 R levels in well-designed, large postmortem brain cohorts are needed to address this issue. Postmortem samples from the dorsolateral prefrontal cortex of 96 schizophrenia subjects and matched controls were collected. Toxicological analyses identified cases who were (AP+) or were not (AP-) receiving antipsychotic treatment near the time of death. Protein and mRNA levels of mGlu2 R and mGlu3 R, as well as GRM2 and GRM3 promoter-attached histone posttranslational modifications, were quantified. Experimental animal models were used to compare with data obtained in human tissues. Compared to matched controls, schizophrenia cortical samples had lower mGlu2 R protein amounts, regardless of antipsychotic medication. Downregulation of mGlu3 R was observed in AP- schizophrenia subjects only. Greater predicted occupancy values of dopamine D2 and serotonin 5HT2A receptors correlated with higher density of mGlu3 R, but not mGlu2 R. Clozapine treatment and maternal immune activation in rodents mimicked the mGlu2 R, but not mGlu3 R regulation observed in schizophrenia brains. mGlu2 R and mGlu3 R mRNA levels, and the epigenetic control mechanisms did not parallel the alterations at the protein level, and in some groups correlated inversely. Insufficient cortical availability of mGlu2 R and mGlu3 R may be associated with schizophrenia. Antipsychotic treatment may normalize mGlu3 R, but not mGlu2 R protein levels. A model in which epigenetic feedback mechanisms controlling mGlu3 R expression are activated to counterbalance mGluR loss of function is described.