Molecular evidence for BDNF-and GABA-related dysfunctions in the amygdala of female subjects with major depression

J. P. Guilloux, G. Douillard-Guilloux, R. Kota, X. Wang, A. M. Gardier, Keri Martinowich, G. C. Tseng, D. A. Lewis, E. Sibille

Research output: Contribution to journalArticle

Abstract

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 (n21 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.

Original languageEnglish (US)
Pages (from-to)1130-1142
Number of pages13
JournalMolecular Psychiatry
Volume17
Issue number11
DOIs
StatePublished - Nov 2012
Externally publishedYes

Fingerprint

Aminobutyrates
Brain-Derived Neurotrophic Factor
Major Depressive Disorder
Amygdala
Depression
Neuropeptide Y
Somatostatin
Genes
Down-Regulation
RNA
Tachykinins
Interneurons
Exons
Proteins
Demography
Gene Expression
Neurons
Polymerase Chain Reaction
Peptides
Brain

Keywords

  • amygdala
  • BDNF
  • female
  • GABA
  • major depression
  • neurotrophic hypothesis
  • somatostatin

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Guilloux, J. P., Douillard-Guilloux, G., Kota, R., Wang, X., Gardier, A. M., Martinowich, K., ... Sibille, E. (2012). Molecular evidence for BDNF-and GABA-related dysfunctions in the amygdala of female subjects with major depression. Molecular Psychiatry, 17(11), 1130-1142. https://doi.org/10.1038/mp.2011.113

Molecular evidence for BDNF-and GABA-related dysfunctions in the amygdala of female subjects with major depression. / Guilloux, J. P.; Douillard-Guilloux, G.; Kota, R.; Wang, X.; Gardier, A. M.; Martinowich, Keri; Tseng, G. C.; Lewis, D. A.; Sibille, E.

In: Molecular Psychiatry, Vol. 17, No. 11, 11.2012, p. 1130-1142.

Research output: Contribution to journalArticle

Guilloux, JP, Douillard-Guilloux, G, Kota, R, Wang, X, Gardier, AM, Martinowich, K, Tseng, GC, Lewis, DA & Sibille, E 2012, 'Molecular evidence for BDNF-and GABA-related dysfunctions in the amygdala of female subjects with major depression', Molecular Psychiatry, vol. 17, no. 11, pp. 1130-1142. https://doi.org/10.1038/mp.2011.113
Guilloux, J. P. ; Douillard-Guilloux, G. ; Kota, R. ; Wang, X. ; Gardier, A. M. ; Martinowich, Keri ; Tseng, G. C. ; Lewis, D. A. ; Sibille, E. / Molecular evidence for BDNF-and GABA-related dysfunctions in the amygdala of female subjects with major depression. In: Molecular Psychiatry. 2012 ; Vol. 17, No. 11. pp. 1130-1142.
@article{266b72b2293d4fe5b1cf3b2b7622d90c,
title = "Molecular evidence for BDNF-and GABA-related dysfunctions in the amygdala of female subjects with major depression",
abstract = "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 (n21 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.",
keywords = "amygdala, BDNF, female, GABA, major depression, neurotrophic hypothesis, somatostatin",
author = "Guilloux, {J. P.} and G. Douillard-Guilloux and R. Kota and X. Wang and Gardier, {A. M.} and Keri Martinowich and Tseng, {G. C.} and Lewis, {D. A.} and E. Sibille",
year = "2012",
month = "11",
doi = "10.1038/mp.2011.113",
language = "English (US)",
volume = "17",
pages = "1130--1142",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - Molecular evidence for BDNF-and GABA-related dysfunctions in the amygdala of female subjects with major depression

AU - Guilloux, J. P.

AU - Douillard-Guilloux, G.

AU - Kota, R.

AU - Wang, X.

AU - Gardier, A. M.

AU - Martinowich, Keri

AU - Tseng, G. C.

AU - Lewis, D. A.

AU - Sibille, E.

PY - 2012/11

Y1 - 2012/11

N2 - 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 (n21 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.

AB - 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 (n21 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.

KW - amygdala

KW - BDNF

KW - female

KW - GABA

KW - major depression

KW - neurotrophic hypothesis

KW - somatostatin

UR - http://www.scopus.com/inward/record.url?scp=84867898404&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867898404&partnerID=8YFLogxK

U2 - 10.1038/mp.2011.113

DO - 10.1038/mp.2011.113

M3 - Article

VL - 17

SP - 1130

EP - 1142

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 11

ER -