|Reduced cortical γ-aminobutyric acid (GABA) levels and altered markers for subpopulations of GABA interneurons have been reported in major depressive disorder (MDD) by in vivo brain imaging and postmortem histological studies. Subgroups of GABA interneurons exert differential inhibitory control on principal pyramidal neurons and can be identified based on the non-overlapping expression of the calcium-binding proteins parvalbumin (PV) or calretinin (CR) or the neuropeptide somatostatin (SST). As altered markers of GABAergic functions may also be present in bipolar disorder (BPD), the specificity of particular GABA-related molecular deficits in mood disorders is not known. We used real-time quantitative polymerase chain reaction (qPCR) to assess expression levels of two GABA synthesizing enzymes (glutamate decarboxylase; GAD65 and GAD67) and of three markers of GABA neuron subpopulations (PV, CR and SST) in the dorsolateral prefrontal cortex (DLPFC; Brodmann area 9) in triads (n=19) of control subjects and matched subjects with BPD or MDD. BPD subjects demonstrated significantly reduced PV mRNA, trend level reduction in SST mRNA and no alterations in GAD67, GAD65, or CR mRNA levels; MDD subjects demonstrated reduced SST mRNA expression without alterations in the other transcripts. The characteristic age-related decline in SST expression was not observed in MDD, as low expression was detected across age in MDD subjects. After controlling for age, MDD subjects demonstrated significantly reduced SST mRNA expression. Decreased SST levels in MDD were confirmed at the protein precursor level (Figure). Results were not explained by other clinical, demographic or technical parameters. In summary, MDD was characterized by low DLPFC SST, whereas decreased PV mRNA appears to distinguish BPD from MDD.