Effect of Antipsychotic Drugs on Group II Metabotropic Glutamate Receptor Expression and Epigenetic Control in Postmortem Brains of Schizophrenia Subjects

Overview

Journal Transl Psychiatry

Specialties Psychiatry
Public Health

Date 2024 Feb 23

PMID 38396013

Authors

Jon DelaCuesta-Barrutia

Oihane Martinez-Peula

Guadalupe Rivero

Jon A Santas-Martin

Eva Munarriz-Cuezva

Iria Brocos-Mosquera

Patricia Miranda-Azpiazu

Rebeca Diez-Alarcia

Benito Morentin

William G Honer

Luis F Callado

Amaia M Erdozain

Alfredo Ramos-Miguel

Affiliations

Soon will be listed here.

Abstract

Antipsychotic-induced low availability of group II metabotropic glutamate receptors (including mGluR and mGluR) in brains of schizophrenia patients may explain the limited efficacy of mGluR ligands in clinical trials. Studies evaluating mGluR 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 mGluR and mGluR, 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 mGluR protein amounts, regardless of antipsychotic medication. Downregulation of mGluR was observed in AP- schizophrenia subjects only. Greater predicted occupancy values of dopamine D and serotonin 5HT receptors correlated with higher density of mGluR, but not mGluR. Clozapine treatment and maternal immune activation in rodents mimicked the mGluR, but not mGluR regulation observed in schizophrenia brains. mGluR and mGluR 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 mGluR and mGluR may be associated with schizophrenia. Antipsychotic treatment may normalize mGluR, but not mGluR protein levels. A model in which epigenetic feedback mechanisms controlling mGluR expression are activated to counterbalance mGluR loss of function is described.

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