Short communicationChanges in levels of cortical metabotropic glutamate 2 receptors with gender and suicide but not psychiatric diagnoses
Introduction
We have reported that, compared to controls, there are lower levels of [3H]LY341495 binding in Brodmann's area (BA) 24, but not BA 17 or 46, from subjects with major depressive disorders (MDD) (McOmish et al., 2016). [3H]LY341495 binding was not altered in those three cortical regions from subjects with bipolar disorders (BD) or schizophrenia. As [3H]LY341495 binds to the mammalian metabotropic glutamate receptors (GRM) 2 and 3 (Johnson et al., 1999, Wright et al., 2001), our data is consistent with the notion that there is a decrease in the total number of GRM2 plus GRM3 in BA 24 from subjects with MDD. Our finding of lower levels of [3H]LY341495 binding in BA 24 from subjects with MDD did not agree with a previous report that levels of [3H]LY341495 binding was not different in BA 24 from subjects with psychotic and non-psychotic depression, BD or schizophrenia (Matosin et al., 2014).
In addition to radioligand binding, a number of studies have measured levels of total GRM2 plus GRM3 protein or GRM2 and GRM3 mRNA in the cortex of subjects with psychiatric disorders. Using antibodies that could not discriminate between GRM2 and GRM3, studies have reported higher levels of total GRM2/3 in BA 10 from subjects with MDD (Feyissa et al., 2010) and either no change (Crook et al., 2002) or higher (Gupta et al., 2005) levels of total GRM2/3 in BA 46 from subjects with schizophrenia. In addition, a study has reported lower levels of GRM3, but not GRM2, mRNA in BA 9 and no changes in levels of GRM2 or GRM3 mRNA in BA 4, 7, 11, 19, 24 and 38 from subjects with schizophrenia (Ghose et al., 2008). Hence, despite radioligand binding, mRNA and protein studies, there is a relative paucity of data specific to levels of cortical GRM2 or GRM3 in the cortex of subjects with psychiatric disorders. In addition, there appears to be no data on individual levels of GRM2 or GRM3 protein in the cortex of subjects with psychiatric disorders.
Given the lack of data on levels of GRM2 and GRM3 protein, and our data on [3H]LY341495 binding, we decided to measure levels of GRM2 in the BA 24 and 46 from subjects with MDD, BD, schizophrenia and a group of age and gender matched controls.
Section snippets
Tissue collection
Consent to collect CNS tissue postmortem was from the Ethics Committee of the Victorian Institute of Forensic Medicine. Tissue collection and processing, case history reviews and diagnostics was as reported previously (McOmish et al., 2016). Hence, case histories were reviewed using the Diagnostic Instrument for Brain studies (Roberts et al., 1998); these data were used by two psychiatrists and a senior psychologist to reach a census diagnoses based on DSM IV criteria. For each case, the left
Antibody validation
The strongest immunogenic band in human cortex for the rabbit anti-GRM2 monoclonal antibody was ∼95 kilodaltons (Supplementary Fig. 1), GRM2 predicted molecular weight. The antibody showed no immunogenic reaction with human serum or when human cortex was probed in the absence of either primary or secondary antibody. In addition, the immunogenic band was present in the membrane, but not the cytosolic, fraction of human cortical homogenate; consistent with GRM2 being a membrane bound protein (
Discussion
Our main finding is that, compared to controls, there were no differences in levels of GRM2 in BA 24 or BA 46 from subjects with MDD, BD or schizophrenia. We had previously reported lower levels of [3H]LY341495 binding in BA 24, but not BA 17 or 46, from subjects with MDD (McOmish et al., 2016). As [3H]LY341495 binds to both GRM2 and 3 (Johnson et al., 1999, Wright et al., 2001) our new data argues that the lower level of radioligand binding in BA 24 in MDD would be consistent with lower levels
Strengths and limitations
Strengths of this study are the use of a validated antibody and tissue from a well-recognised brain bank to, for the first time, measure levels of GRM2 protein in cortex from subjects with mood disorders and schizophrenia. Limitations of this study are relatively small diagnostic cohorts which limits exploration of differences in gender and suicide completion within psychiatric groups. There is potential for drug treatment effects as a confound.
Conclusions
In conclusion, our data suggests higher levels of GRM2 in BA 46 from males compared to females and in suicide completers. Combining the data in BA 24 from subjects with MDD with our data show2ing lower levels of [3H]LY341495 binding to GRM2/3 suggest GRM3 must be lower in BA 24 in MDD. Our data adds to the notion that altered glutamatergic neurotransmission contributing to an increased level of suicide completion (Ernst et al., 2009).
Conflict of interest
The authors have no conflicts of interest.
Contributors role
All authors were involved in the design of these studies and subsequent data interpretation. BD completed all statistical analyses. CD and AG carried out experimental procedures. All authors contributed to producing the final form of the submitted manuscript.
Funding
This work was supported by the National Medical & Health Research Council (grant numbers 1025774, 566967, 1002240), the CRC for Mental Health, One in Five and the Andrew and Claire Heenan Ride for Ben as well as Operational Infrastructure Support from the Victorian State Government. None of the funding bodies had any influence over the research activity that produced the data reported.
Acknowledgement
We thank Geoff Pavey for his curation of the postmortem human tissue received from the Victorian Brain Bank Network.
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