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Antipsychotic-induced low availability of group II metabotropic glutamate receptors (including mGlu 2 R and mGlu 3 R) in brains of schizophrenia patients may explain the limited efficacy of mGlu 2/3 R ligands in clinical trials. Studies evaluating mGlu 2/3 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 mGlu 2 R and mGlu 3 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 mGlu 2 R protein amounts, regardless of antipsychotic medication. Downregulation of mGlu 3 R was observed in AP- schizophrenia subjects only. Greater predicted occupancy values of dopamine D 2 and serotonin 5HT 2A receptors correlated with higher density of mGlu 3 R, but not mGlu 2 R. Clozapine treatment and maternal immune activation in rodents mimicked the mGlu 2 R, but not mGlu 3 R regulation observed in schizophrenia brains. mGlu 2 R and mGlu 3 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 mGlu 2 R and mGlu 3 R may be associated with schizophrenia. Antipsychotic treatment may normalize mGlu 3 R, but not mGlu 2 R protein levels. A model in which epigenetic feedback mechanisms controlling mGlu 3 R expression are activated to counterbalance mGluR loss of function is described., (© 2024. The Author(s).)

Previous evidence suggests that α 2 -adrenoceptors (α 2 -AR) may be involved in the pathophysiology of schizophrenia. However, postmortem brain studies on α 2 -AR expression and functionality in schizophrenia are scarce. The aim of our work was to evaluate α 2A -AR and α 2C -AR expression in different subcellular fractions of prefrontal cortex postmortem tissue from antipsychotic-free (absence of antipsychotics in blood at the time of death) (n = 12) and antipsychotic-treated (n = 12) subjects with schizophrenia, and matched controls (n = 24). Functional coupling of α 2 -AR to G α proteins induced by the agonist UK14304 was also tested. Additionally, G α protein expression was also evaluated. In antipsychotic-free schizophrenia subjects, α 2A -AR and α 2C -AR protein expression was similar to controls in all the subcellular fractions. Conversely, in antipsychotic-treated schizophrenia subjects, increased α 2A -AR expression was found in synaptosomal plasma membrane and postsynaptic density (PSD) fractions (+60% and +79% vs controls, respectively) with no significant changes in α 2C -AR. [ 35 S]GTPγS SPA experiments showed a significant lower stimulation of G αi2 and G αi3 proteins by UK14304 in antipsychotic-treated schizophrenia subjects, whereas stimulation in antipsychotic-free schizophrenia subjects remained unchanged. G αo protein stimulation was significantly decreased in both antipsychotic-free and antipsychotic-treated schizophrenia subjects compared to controls. Expression of G αi3 protein did not differ between groups, whereas G αi2 levels were increased in PSD of schizophrenia subjects, both antipsychotic-free and antipsychotic-treated. G αo protein expression was increased in PSD of antipsychotic-treated subjects and in the presynaptic fraction of antipsychotic-free schizophrenia subjects. The present results suggest that antipsychotic treatment is able to modify in opposite directions both the protein expression and the functionality of α 2A -AR in the cortex of schizophrenia patients., (Copyright © 2021. Published by Elsevier B.V.)

Schizophrenia has been associated with alterations in neurotransmission and synaptic dysfunction. Spinophilin is a multifunctional scaffold protein that modulates excitatory synaptic transmission and dendritic spine morphology. Spinophilin can also directly interact with and regulate several receptors for neurotransmitters, such as dopamine D 2 receptors, which play a role in the pathophysiology of schizophrenia and are targets of antipsychotics. Several studies have thus suggested an implication of spinophilin in schizophrenia. In the present study spinophilin protein expression was determined by western blot in the postmortem dorsolateral prefrontal cortex of 24 subjects with schizophrenia (12 antipsychotic-free and 12 antipsychotic-treated subjects) and 24 matched controls. Experiments were performed in synaptosomal membranes (SPM) and in postsynaptic density fractions (PSD). As previously reported, two specific bands for this protein were observed: an upper 120-130 kDa band and a lower 80-95 kDa band. The spinophilin lower band showed a significant decrease in schizophrenia subjects compared to matched controls, both in SPM and PSD fractions (-15%, p = 0.007 and -15%, p = 0.039, respectively). When schizophrenia subjects were divided by the presence or absence of antipsychotics in blood at death, the lower band showed a significant decrease in antipsychotic-treated schizophrenia subjects (-24%, p = 0.003 for SPM and -26%, p = 0.014 for PSD), but not in antipsychotic-free subjects, compared to their matched controls. These results suggest that antipsychotics could produce alterations in spinophilin expression that do not seem to be related to schizophrenia per se. These changes may underlie some of the side effects of antipsychotics., Competing Interests: Conflict of interest Authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)