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.
  
  
  METHODS
  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.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Tripp
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Oh
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Guilloux
authors.forename: Keri
authors.initials: K
authors.lastname: Martinowich
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
authors.forename: Etienne
authors.initials: E
authors.lastname: Sibille
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000502:physiology*; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D004292:Dominance, Cerebral / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D005091:Exons / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D006580:Genetic Carrier Screening; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000502:physiology; D006179:Gyrus Cinguli / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics*; D020813:Receptor, trkB / Q000235:genetics / Q000502:physiology; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D005680:gamma-Aminobutyric Acid; D020813:Receptor, trkB; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2