Feature Finding Figure
The subgenual anterior cingulate cortex (sgACC) is implicated in major depressive disorder (MDD) pathology and treatment response. Low brain-derived neurotrophic factor (BDNF) and reduced markers for gamma-amino butyric acid (GABA) function are reported in MDD, including in amygdala, but their contribution to sgACC dysfunction is not known. Using PCR, 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 cingulate cortex of mice with reduced BDNF function (BDNF-heterozygous, Bdnf+/-; BDNF exon IV-knockout, Bdnf-KIV). Gene expression was then quantified in sgACC of postmortem MDD and control subjects (n=51/group; 49% female) and compared to prior amygdala results. Studies in Bdnf+/- and Bdnf-KIV mice sorted genes in high, intermediate or no BDNFdependency sets. In MDD, BDNF receptor (TRKB) expression, but not BDNF was reduced. Postmortem MDD subjects exhibited downregulations in genes with high and intermediate BDNF-dependency, including markers of dendritic-targeting interneurons (SST, NPY, CORT; figure) and GABA synthesizing enzyme (GAD2). Changes extended to BDNF-independent genes (PVALB, GAD1). Changes were greater in men (potentially due to low baseline expression in women), showed notable differences with prior amygdala results, and besides sex were not explained by other demographic or clinical factors. Parallel human/mouse studies provide direct (low TRKB) and indirect (low expression of BDNF-dependent genes) evidence in support of decreased BDNF signaling in sgACC of MDD subjects, implicate dendritic-targeting GABA neurons and GABA synthesis, and together suggest a common BDNF/GABA-related pathology in MDD with gender- and brain region-specific features.
Tripp AC, Oh H, Guilloux JP, Martinowich K, Lewis DA, Sibille E: BDNF Signaling and Subgenual Anterior Cingulate Cortex Dysfunction in Major Depression. Am J Psychiatry, 69(11):1194-202, 2012.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
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