title: Sex differences in glutamate receptor gene expression in major depression and suicide.
abstract: Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59=2.32, P=0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups. These data reveal further evidence that, in addition to the NMDA receptor, the AMPA, kainate and the metabotropic GluRs may be targets for the development of rapidly acting antidepressant drugs.
authors.affiliation: Department of Pharmacy Practice and Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Gray
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.|Departments of Neurology and Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Hyde
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Deep-Soboslay
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Kleinman
authors.affiliation: Department of Pharmacy Practice and Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.|Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: M S
authors.identifier: http://orcid.org/0000-0002-8261-3040
authors.initials: MS
authors.lastname: Sodhi
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000235:genetics / Q000378:metabolism* / Q000523:psychology*; D005260:Female; D015870:Gene Expression; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use; D008297:Male; D017397:Prefrontal Cortex / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000096:biosynthesis* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012737:Sex Factors; D013405:Suicide / Q000523:psychology*; D059467:Transcriptome
chemical_list: D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D007649:Ketamine