Reduced somatostatin in subgenual anterior cingulate cortex in major depression

Abstract

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.

Figure 1. SST Transcript Expression is Reduced in MDD Subjects

SST expression (in relative expression of the control group mean) is displayed for each control (circles) and MDD subject (triangles) in the combined group (A) and in the male (B) and female (C) cohorts. The mean value is shown for each subject group (black hash marks). Standard deviation is shown in red. *, p<0.05; **, p<0.01 (ANCOVA analysis).

Figure 2. SST Transcript Inverse Correlation with Age is reduced in females and in MDD

mRNA signal and trendline are shown for control subjects (circles) in black, and in red for controls (triangles). A) In the male/female combined group, SST expression is significantly inversely correlated with age in control subjects (R=−0.357; p=0.005), but not in MDD subjects (R=−0.104; p=0.234). B) In the male cohort SST expression is significantly inversely correlated with age (R=−0.509, p=0.004), but not in MDD subjects (R=−0.143; p=0.243). C) In the female cohort, SST expression is inversely correlated with age at the trend level in control subjects (R=−0.278; p=0.089), and not in MDD subjects (R=−0.116; p=0.291).

Figure 3. Protein Expression of the SST precursor is Reduced in MDD Subjects

(A) SST precursor protein relative immunoreactivity migrates at the expected ~14kD size (left; see methods). Examples of control (C) and MDD (D) paired samples run on the same gel. (B) The log₂ ratio (left Y-axis) and fold reduction (right Y-axis) of MDD/Control are shown for each pair in all samples, male subjects, and female subjects. Standard deviation is shown in red, log₂ ratio mean reduction is shown in black. (*,p<0.05; **p<0.01; ***p<0.001: see text).