Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder

Adam Tripp, Hyunjung Oh, Jean Philippe Guilloux, Keri Martinowich, David A. Lewis, Etienne Sibille

Research output: Contribution to journalArticle

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 [BdnfKIV] 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 BdnfKIV 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.

Original languageEnglish (US)
Pages (from-to)1194-1202
Number of pages9
JournalAmerican Journal of Psychiatry
Volume169
Issue number11
DOIs
StatePublished - Nov 1 2012

Fingerprint

Gyrus Cinguli
Brain-Derived Neurotrophic Factor
Major Depressive Disorder
gamma-Aminobutyric Acid
Amygdala
Genes
Depression
trkB Receptor
Pathology
Sex Factors
GABAergic Neurons
Interneurons
Neuropeptides
Knockout Mice
Exons
Down-Regulation
Demography

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder. / Tripp, Adam; Oh, Hyunjung; Guilloux, Jean Philippe; Martinowich, Keri; Lewis, David A.; Sibille, Etienne.

In: American Journal of Psychiatry, Vol. 169, No. 11, 01.11.2012, p. 1194-1202.

Research output: Contribution to journalArticle

Tripp, Adam ; Oh, Hyunjung ; Guilloux, Jean Philippe ; Martinowich, Keri ; Lewis, David A. ; Sibille, Etienne. / Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder. In: American Journal of Psychiatry. 2012 ; Vol. 169, No. 11. pp. 1194-1202.
@article{d88151297cbb4fcf872db63885155b31,
title = "Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder",
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 [BdnfKIV] 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 BdnfKIV 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.",
author = "Adam Tripp and Hyunjung Oh and Guilloux, {Jean Philippe} and Keri Martinowich and Lewis, {David A.} and Etienne Sibille",
year = "2012",
month = "11",
day = "1",
doi = "10.1176/appi.ajp.2012.12020248",
language = "English (US)",
volume = "169",
pages = "1194--1202",
journal = "American Journal of Psychiatry",
issn = "0002-953X",
publisher = "American Psychiatric Association",
number = "11",

}

TY - JOUR

T1 - Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder

AU - Tripp, Adam

AU - Oh, Hyunjung

AU - Guilloux, Jean Philippe

AU - Martinowich, Keri

AU - Lewis, David A.

AU - Sibille, Etienne

PY - 2012/11/1

Y1 - 2012/11/1

N2 - 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 [BdnfKIV] 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 BdnfKIV 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.

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 [BdnfKIV] 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 BdnfKIV 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.

UR - http://www.scopus.com/inward/record.url?scp=84868599247&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84868599247&partnerID=8YFLogxK

U2 - 10.1176/appi.ajp.2012.12020248

DO - 10.1176/appi.ajp.2012.12020248

M3 - Article

C2 - 23128924

AN - SCOPUS:84868599247

VL - 169

SP - 1194

EP - 1202

JO - American Journal of Psychiatry

JF - American Journal of Psychiatry

SN - 0002-953X

IS - 11

ER -