Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder

Abstract

Objective: The subgenual anterior cingulate cortex is implicated in the pathology and treatment response of major depressive disorder. Low levels of brain-derived neurotrophic factor (BDNF) and reduced markers for GABA function, including in the amygdala, are reported in major depression, but their contribution to subgenual anterior cingulate cortex dysfunction is not known.

Method: Using polymerase chain reaction, we first assessed the degree to which BDNF controls mRNA expression (defined as BDNF dependency) of 15 genes relating to GABA and neuropeptide functions in the cingulate cortex of mice with reduced BDNF function (BDNF-heterozygous [Bdnf(+/-)] mice and BDNF exon-IV knockout [Bdnf(KIV)] mice). Gene expression was then quantified in the subgenual anterior cingulate cortex of 51 postmortem subjects with major depressive disorder and comparison subjects (total subjects, N=102; 49% were women) and compared with previous amygdala results.

Results: Based on the results in Bdnf(+/-) and Bdnf(KIV) mice, genes were sorted into high, intermediate, and no BDNF dependency sets. In postmortem human subjects with major depression, BDNF receptor (TRKB) expression, but not BDNF, was reduced. Postmortem depressed subjects exhibited down-regulation in genes with high and intermediate BDNF dependency, including markers of dendritic targeting interneurons (SST, NPY, and CORT) and a GABA synthesizing enzyme (GAD2). Changes extended to BDNF-independent genes (PVALB and GAD1). Changes were greater in men (potentially because of low baseline expression in women), displayed notable differences from prior amygdala results, and were not explained by demographic or clinical factors other than sex.

Conclusions: These parallel human/mouse analyses provide direct (low TRKB) and indirect (low expression of BDNF-dependent genes) evidence in support of decreased BDNF signaling in the subgenual anterior cingulate cortex in individuals with major depressive disorder, implicate dendritic targeting GABA neurons and GABA synthesis, and, together, suggest a common BDNF-/GABA-related pathology in major depression with sex- and brain region-specific features.

FIGURE 1. Significant Sex Differences in Gene Expression in Postmortem Comparison Subjects^a

^a Comparisons are between male and female comparison subjects without psychiatric diagnoses. SST mRNA expression was lower in female subjects at a level that fell short of significance (p<0.1). Black bars indicate mean values, and red bars indicate the coefficients of variation. The asterisk indicates statistical significance (p<0.05).

FIGURE 2. BDNF/TRKB and Associated GABA Marker Dysregulation in the Subgenual Anterior Cingulate Cortex and Amygdala in Postmortem Subjects With Major Depressive Disorder^a

^a Reduced BDNF signaling in major depressive disorder is suggested by the findings of low BDNF in the amygdala and low TrkB in the subgenual anterior cingulate cortex. Analyses of mice with reduced BDNF functions suggest that co-occurring GABA-related gene changes are partly downstream from low BDNF signaling, but the exact nature and extent of downstream gene changes are moderated by brain region- and sex-specific factors. Comparison findings in the amygdala are taken from a previous study (12). SgACC=Subgenual anterior cingulate cortex.