Faculty Collaboration Database

Evidence revealing deregulation of the KLF11-MAO A pathway in association with chronic stress and depressive disorders. Neuropsychopharmacology 2015 May;40(6):1373-82

Date

12/17/2014

Pubmed ID

25502632

Pubmed Central ID

PMC4397395

DOI

10.1038/npp.2014.321

Scopus ID

2-s2.0-84939985471 (requires institutional sign-in at Scopus site)   31 Citations

Abstract

The biochemical pathways underlying major depressive disorder (MDD) and chronic stress are not well understood. However, it has been reported that monoamine oxidase A (MAO A, a major neurotransmitter-degrading enzyme) is significantly increased in the brains of human subjects affected with MDD and rats exposed to chronic social defeat (CSD) stress, which is used to model depression. In the current study, we compared the protein levels of a MAO A-transcriptional activator, Kruppel-like factor 11 (KLF11 , also recognized as transforming growth factor-beta-inducible early gene 2) between the brains of 18 human subjects with MDD and 18 control subjects. We found that, indeed, the expression of KLF11 is increased by 36% (p<0.02) in the postmortem prefrontal cortex of human subjects with MDD compared with controls. We also observed a positive correlation between KLF11 levels and those of its target gene, MAO A, both in association with MDD. KLF11 protein expression was also increased by 44% (p<0.02) in the frontal cortex of KLF11 wild-type mice (Klf11(+/+)) vs Klf11(-/-) when both exposed to CSD stress. In contrast, locomotor activities, central box duration and sucrose preference were significantly reduced in the stressed Klf11(+/+) mice, suggesting that Klf11(+/+) mice are more severely affected by the stress model compared with Klf11(-/-) mice. These results serve to assign an important role of KLF11 in upregulating MAO A in MDD and chronic social stress, suggesting that inhibition of the pathways regulated by this transcription factor may aid in the therapeutics of neuropsychiatric illnesses. Thus, the new knowledge derived from the current study extends our understanding of transcriptional mechanisms that are operational in the pathophysiology of common human diseases and thus bears significant biomedical relevance.

Author List

Harris S, Johnson S, Duncan JW, Udemgba C, Meyer JH, Albert PR, Lomberk G, Urrutia R, Ou XM, Stockmeier CA, Wang JM

Author

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis Regulatory Proteins
Cell Cycle Proteins
Chronic Disease
DNA-Binding Proteins
Depressive Disorder, Major
Disease Models, Animal
Dominance-Subordination
Female
Frontal Lobe
Humans
Male
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Monoamine Oxidase
Motor Activity
Repressor Proteins
Severity of Illness Index
Stress, Psychological
Transcription Factors
Up-Regulation