Reduced somatostatin in subgenual anterior cingulate cortex in major depression

Converging evidence suggests a central role for dysfunction of the subgenual anterior cingulate cortex (sgACC) in the pathophysiology of major depressive disorder (MDD). Underlying mechanisms may include altered GABAergic function. Expression of somatostatin (SST), an inhibitory neuropeptide localized to a subset of GABA neurons, has been shown to be lower in the dorsolateral prefrontal cortex of male MDD subjects. Here, to investigate whether alterations in SST may contribute to sgACC dysfunction in MDD, and whether the alterations display sex-specificity, we measured sgACC SST at the mRNA and precursor peptide levels in a large cohort of subjects with MDD. SST mRNA levels were analyzed by quantitative PCR (qPCR) in the postmortem sgACC from male (n = 26) and female (n = 25) subjects with MDD and sex-matched subjects with no psychiatric diagnosis (n = 51). Prepro-SST protein levels were assessed in a subset of subjects (n = 42 pairs) by semi-quantitative Western blot. The mRNA expression of SST was significantly reduced by 38% in female subjects and by 27% in male subjects with MDD. The characteristic age-related decline in SST expression was observed in control (Pearson R = − 0.357, p = 0.005) but not MDD (R = − 0.104, p = 0.234) subjects, as low expression was detected across ages in MDD subjects. Protein expression was similarly reduced by 19% in both MDD groups, and findings were more robust in female (p = 0.0056) than in males (p = 0.0373) compared to respective controls. In conclusion, low SST represents a robust pathological finding in MDD. Specifically, alterations in SST signaling and/or SST-bearing GABA neurons may represent a critical pathophysiological entity that contributes to sgACC dysfunction and that matches to the high female vulnerability to develop MDD.

Research Highlights
► Somatostatin (SST) mRNA and protein level is reduced in the subgenual anterior cingulate cortex (sgACC) of subjects with MDD.
► SST mRNA decreases with age in control but not in MDD subjects.
► SST mRNA reduction is more robust in female compared to male subjects with MDD.
► Low cortical SST may represent part of a molecular phenotype of major depression.
► Low SST may provide a molecular lead to characterize the GABA-related microcircuitry deficits in major depression.