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Experimental Brain Research

, Volume 237, Issue 12, pp 3419–3430 | Cite as

Increased expression of plasminogen activator inhibitor-1 (PAI-1) is associated with depression and depressive phenotype in C57Bl/6J mice

  • René A. Girard
  • Prashant S. Chauhan
  • Torry A. Tucker
  • Tim Allen
  • Jaswinder Kaur
  • Ann Jeffers
  • Kathleen Koenig
  • Galina Florova
  • Andrey A. Komissarov
  • Tatiana A. Gaidenko
  • Mignote B. Chamiso
  • James Fowler
  • Danna E. Morris
  • Krishna Sarva
  • Karan P. Singh
  • Steven Idell
  • Richard D. IdellEmail author
Research Article
  • 88 Downloads

Abstract

Plasminogen activator inhibitor 1 (PAI-1), which is elevated in numerous disease states, has been implicated as a stress-related protein involved in the pathogenesis of depression. We measured PAI-1 in the plasma of healthy and depressed individuals and assessed plasminogen activator (PA) expression and regulation by PAI-1 in cultured normal human astrocytes (NHA). Elevated plasma PAI-1 levels were found in depressed patients. Brain tissues from depressed individuals also showed stronger expression of hippocampal PAI-1 by confocal imaging in comparison to healthy individuals. Using a lipopolysaccharide-induced inflammatory model of depression in mice, we measured PAI-1 in murine plasma and brain, by ELISA and immunohistochemistry, respectively. Similar elevations were seen in plasma but not in brain homogenates of mice exposed to LPS. We further correlated the findings with depressive behavior. Ex vivo experiments with NHA treated with proinflammatory cytokines implicated in the pathogenesis of depression showed increased PAI-1 expression. Furthermore, these studies suggest that urokinase-type plasminogen activator may serve as an astrocyte PA reservoir, able to promote cleavage of brain-derived neurotrophic factor (BDNF) during stress or inflammation. In summary, our findings confirm that derangements of PAI-1 variably occur in the brain in association with the depressive phenotype. These derangements may impede the availability of active, mature (m)BDNF and thereby promote a depressive phenotype.

Keywords

Depression Fibrinolysis Hippocampus Inflammation LPS PAI-1 

Notes

Acknowledgements

We thank University of Miami Brain Endowment Bank “a National Institutes of Health NeuroBioBank” for providing control and MDD brain samples. This work was supported by a grant from Department of Behavioral Health Institutional Funding and Texas Workforce Commission (No. TWC12345) and Institutional Funding from The University of Texas Health Science Center Tyler.

Compliance with ethical standards

Conflict of interest

The authors have no financial conflicts of interest to report.

Supplementary material

221_2019_5682_MOESM1_ESM.docx (53 kb)
Supplementary material 1 (DOCX 52 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • René A. Girard
    • 1
  • Prashant S. Chauhan
    • 1
  • Torry A. Tucker
    • 1
  • Tim Allen
    • 2
  • Jaswinder Kaur
    • 2
  • Ann Jeffers
    • 1
  • Kathleen Koenig
    • 1
  • Galina Florova
    • 1
  • Andrey A. Komissarov
    • 1
  • Tatiana A. Gaidenko
    • 1
  • Mignote B. Chamiso
    • 1
  • James Fowler
    • 1
  • Danna E. Morris
    • 1
  • Krishna Sarva
    • 1
  • Karan P. Singh
    • 3
  • Steven Idell
    • 1
  • Richard D. Idell
    • 4
    Email author
  1. 1.Department of Cellular and Molecular BiologyThe University of Texas Health Science Center at TylerTylerUSA
  2. 2.Department of PathologyThe University of Mississippi Medical CenterJacksonUSA
  3. 3.Department of Epidemiology and BiostatisticsSchool of Rural and Community Health, The University of Texas Health Science Center at TylerTylerUSA
  4. 4.Department of Behavioral Health, Child and Adolescent PsychiatryThe University of Texas Health Science Center at TylerTylerUSA

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