PMID- 23128924 OWN - NLM STAT- MEDLINE DCOM- 20130327 LR - 20211021 IS - 1535-7228 (Electronic) IS - 0002-953X (Print) IS - 0002-953X (Linking) VI - 169 IP - 11 DP - 2012 Nov TI - Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder. PG - 1194-202 LID - 10.1176/appi.ajp.2012.12020248 [doi] AB - 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. FAU - Tripp, Adam AU - Tripp A AD - Department of Psychiatry, University of Pittsburgh, USA. FAU - Oh, Hyunjung AU - Oh H FAU - Guilloux, Jean-Philippe AU - Guilloux JP FAU - Martinowich, Keri AU - Martinowich K FAU - Lewis, David A AU - Lewis DA FAU - Sibille, Etienne AU - Sibille E LA - eng GR - R01 MH077159/MH/NIMH NIH HHS/United States GR - MH-084053/MH/NIMH NIH HHS/United States GR - MH-084060/MH/NIMH NIH HHS/United States GR - MH-085111/MH/NIMH NIH HHS/United States GR - P50 MH084053/MH/NIMH NIH HHS/United States GR - R21 MH085111/MH/NIMH NIH HHS/United States GR - K02 MH084060/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - United States TA - Am J Psychiatry JT - The American journal of psychiatry JID - 0370512 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (RNA, Messenger) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 4.1.1.15 (Glutamate Decarboxylase) RN - EC 4.1.1.15 (glutamate decarboxylase 2) SB - IM CIN - Am J Psychiatry. 2012 Nov;169(11):1137-40. PMID: 23128919 MH - Animals MH - Brain-Derived Neurotrophic Factor/*genetics/*physiology MH - Case-Control Studies MH - Depressive Disorder, Major/*genetics/pathology/*physiopathology MH - Dominance, Cerebral/genetics MH - Down-Regulation/genetics/physiology MH - Exons/genetics MH - Female MH - Gene Expression/genetics/physiology MH - Genetic Carrier Screening MH - Glutamate Decarboxylase/genetics/physiology MH - Gyrus Cinguli/pathology/*physiopathology MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Polymerase Chain Reaction MH - RNA, Messenger/*genetics MH - Receptor, trkB/genetics/physiology MH - Sex Factors MH - Signal Transduction/*physiology MH - gamma-Aminobutyric Acid/physiology PMC - PMC3638149 MID - NIHMS454352 COIS- Dr. Lewis currently receives investigator-initiated research support from Bristol-Myers Squibb, the Bristol-Myers Squibb Foundation, Curridium, Ltd., and Pfizer; he has also previously served as a consultant to Bristol-Myers Squibb in the areas of target identification and validation and new compound development. The other authors report no financial relationships with commercial interest. EDAT- 2012/11/07 06:00 MHDA- 2013/03/28 06:00 PMCR- 2013/11/01 CRDT- 2012/11/07 06:00 PHST- 2012/11/07 06:00 [entrez] PHST- 2012/11/07 06:00 [pubmed] PHST- 2013/03/28 06:00 [medline] PHST- 2013/11/01 00:00 [pmc-release] AID - 1389522 [pii] AID - 10.1176/appi.ajp.2012.12020248 [doi] PST - ppublish SO - Am J Psychiatry. 2012 Nov;169(11):1194-202. doi: 10.1176/appi.ajp.2012.12020248.