Cited by 273Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

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Brain-Derived Neurotrophic Factor Signaling and Subgenual Anterior Cingulate Cortex Dysfunction in Major Depressive Disorder

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Tripp, Adam, Oh, Hyunjung, Guilloux, Jean-Philippe, Martinowich, Keri, Lewis, David A., Sibille, Etienne·2012·American Journal of Psychiatry

DOI 10.1176/appi.ajp.2012.12020248PMC PMC3638149

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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.

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Authors: Tripp, A., Oh, H., Guilloux, J.-P., Martinowich, K., Lewis, D. A., & Sibille, E.
Affiliations: Université Paris-Sud (FR)
ORCID: Oh, Hyunjung
Guilloux, Jean-Philippe
Martinowich, Keri
Lewis, David A.
Sibille, Etienne
Venue: American Journal of Psychiatry
Publisher: American Psychiatric Association Publishing
Published: 2012-11
Volume: 169
Issue: 11
Pages: 1194-1202
ISSN: 0002-953X (ISSN-L)
1535-7228
DOI: 10.1176/appi.ajp.2012.12020248
PMC: PMC3638149
OpenAlex: W2161401578
Cited by: 273
References: 40
Citations by year: 2026: 10 · 2025: 12 · 2024: 32 · 2023: 18 · 2022: 18 · 2021: 24 · 2020: 24 · 2019: 24 · 2018: 21 · 2017: 18 · 2016: 18 · 2015: 19 · 2014: 24 · 2013: 10 · 2012: 1
FWCI: 12.70
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: American Journal of Psychiatry (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Mental Health (P50MH084053, MH084060, MH084053, MH085111, R21MH085111, R01MH077159, K02MH084060)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: major depressive disorder, brain-derived neurotrophic factor, subgenual anterior cingulate cortex, TrkB receptor, GABAergic interneurons, GABA synthesis, gene expression, sex differences, postmortem brain, amygdala, neuropeptides
MeSH terms: Animals, Major Depressive Disorder, Depressive Disorder, Major, Dominance, Cerebral, Exons, Female, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Gyrus Cinguli, Genetic Carrier Screening, Humans, Male, Mice, Inbred C57BL, RNA, Messenger, Sex Factors, Signal Transduction, Down-Regulation, Gene Expression, Case-Control Studies, Polymerase Chain Reaction, Mice, Knockout, Brain-Derived Neurotrophic Factor, Receptor, trkB, Mice

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Brain-Derived Neurotrophic Factor Signaling and Subgenual Anterior Cingulate Cortex Dysfunction in Major Depressive Disorder

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