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
