Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression
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Women are twice as likely as men to develop major depressive disorder (MDD) and are more prone to recurring episodes. Hence, we tested the hypothesis that the illness may associate with robust molecular changes in female subjects, and investigated large-scale gene expression in the post-mortem brain of MDD subjects paired with matched controls (n=21 pairs). We focused on the lateral/basolateral/basomedian complex of the amygdala as a neural hub of mood regulation affected in MDD. Among the most robust findings were downregulated transcripts for genes coding for γ-aminobutyric acid (GABA) interneuron-related peptides, including somatostatin (SST), tachykinin, neuropeptide Y (NPY) and cortistatin, in a pattern reminiscent to that previously reported in mice with low brain-derived neurotrophic factor (BDNF). Changes were confirmed by quantitative PCR and not explained by demographic, technical or known clinical parameters. BDNF itself was significantly downregulated at the RNA and protein levels in MDD subjects. Investigating putative mechanisms, we show that this core MDD-related gene profile (including SST, NPY, TAC1, RGS4 and CORT) is recapitulated by complementary patterns in mice with constitutive (BDNF-heterozygous) or activity-dependent (exon IV knockout) decreases in BDNF function, with a common effect on SST and NPY. Together, these results provide both direct (low RNA/protein) and indirect (low BDNF-dependent gene pattern) evidence for reduced BDNF function in the amygdala of female subjects with MDD. Supporting studies in mutant mice models suggest a complex mechanism of low constitutive and activity-dependent BDNF function in MDD, particularly affecting SST/NPY-related GABA neurons, thus linking the neurotrophic and GABA hypotheses of depression.
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Changes in PV expression are less consistent.
“Decreases in SST expression are detected in the dorsolateral prefrontal cortex and subgenual anterior cingulate cortex of depressed patients as well as the prefrontal cortex of mice exposed to chronic unpredictable stress, while changes in PV are less consistent [134-136].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [135]
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- Authors
- Guilloux, J.-P., Douillard-Guilloux, G., Kota, R., Wang, X., Gardier, A. M., Martinowich, K., Tseng, G. C., Lewis, D. A., & Sibille, E.
- Affiliations
- University of Pittsburgh (US)
- Université Paris-Sud (FR)
- National Institute of Mental Health (US)
- Corresponding author
- Sibille, E
- Venue
- Molecular Psychiatry
- Published
- 2011-09-13
- Volume
- 17
- Issue
- 11
- Pages
- 1130-1142
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3237836
- OpenAlex
- W2136371177
- Cited by
- 378
- References
- 92
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 35 · 2023: 32 · 2022: 23 · 2021: 37 · 2020: 26 · 2019: 39 · 2018: 30 · 2017: 20 · 2016: 27 · 2015: 30 · 2014: 19 · 2013: 19 · 2012: 12
- FWCI
- 11.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (P50MH084053, MH084060, MH084053, MH085111, R01MH051234, R21MH085111, R01MH077159, K02MH084060)
- Topics
- Health Sciences › Medicine › Pharmacology › 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, depression in women, amygdala, brain-derived neurotrophic factor, GABAergic interneurons, somatostatin, neuropeptide Y, cortistatin, tachykinins, RGS4, gene expression, postmortem brain, sex differences
- MeSH terms
- Adolescent, Adult, Aged, Amygdala, Animals, Major Depressive Disorder, Female, Humans, Middle Aged, Neuropeptide Y, Neuropeptides, Somatostatin, Tachykinins, Down-Regulation, Case-Control Studies, Mice, Knockout, Brain-Derived Neurotrophic Factor, Gene Expression Profiling, Mice, Genetic Association Studies, GABAergic Neurons
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