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Brain-Derived Neurotrophic Factor Signaling and Subgenual Anterior Cingulate Cortex Dysfunction in Major Depressive Disorder
Open accessAbstract
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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“Immunohistochemical analysis of interneurons and transcripts of interneuron-associated proteins are decreased within the PFC and anterior cingulate cortex in human MDD brain tissue and in chronically stressed rats, suggesting that deficits in GABA levels may contribute to the symptoms of depression [205][206][207][208].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [207]
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“Postmortem studies have demonstrated that patients with depression and related mental illnesses have lower BDNF and/or TRKB mRNA levels (75–77), reduced cortical neuron size (75, 78, 79), lower synaptic protein levels (80), decreased mTOR signaling (81), and fewer dendritic spines/synapses (82, 83) in the PFC.”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [77]
Experimental — accuracy not yet measuredIn the citing paper
“Immunohistochemical analysis of interneurons and transcripts of interneuron-associated proteins are decreased within the PFC and anterior cingulate cortex in human MDD brain tissue and in chronically stressed rats, suggesting that deficits in GABA levels may contribute to the symptoms of depression [205][206][207][208].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [207]
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Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression
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The GABAergic deficit hypothesis of major depressive disorder
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Research works printed but not linked: 1
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Sorted by citations
Duman, R. S., Sanacora, G., & Krystal, J. H. (2019) · Neuron · doi:10.1016/j.neuron.2019.03.013 · Cited by 1,026
Sex-specific transcriptional signatures in human depression
Labonté, B., Engmann, O., Purushothaman, I., Menard, C., Wang, J., Tan, C., Scarpa, J. R., Moy, G., Loh, Y.-H. E., Cahill, M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4386 · Cited by 748
Astrocyte Pathology in Major Depressive Disorder: Insights from Human Postmortem Brain Tissue
Rajkowska, G., & Stockmeier, C. (2013) · Current Drug Targets · doi:10.2174/13894501113149990156 · Cited by 603
Brain-Derived Neurotrophic Factor Signaling in Depression and Antidepressant Action
Castrén, E., & Monteggia, L. M. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.05.008 · Cited by 540
Sex differences in depression: Insights from clinical and preclinical studies
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Metadata
- Authors
- Tripp, A., Oh, H., Guilloux, J.-P., Martinowich, K., Lewis, D. A., & Sibille, E.
- Affiliations
- Université Paris-Sud (FR)
- Venue
- American Journal of Psychiatry
- Published
- 2012-11
- Volume
- 169
- Issue
- 11
- Pages
- 1194-1202
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- 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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