Exp Brain Res. 2019 Dec;237(12):3419-3430. doi: 10.1007/s00221-019-05682-0. Epub 2019 Nov 16.

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

Girard RA1, Chauhan PS1, Tucker TA1, Allen T2, Kaur J2, Jeffers A1, Koenig K1, Florova G1, Komissarov AA1, Gaidenko TA1, Chamiso MB1, Fowler J1, Morris DE1, Sarva K1, Singh KP3, Idell S1, Idell RD4.

Author information

1

Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX, 75708, USA.

2

Department of Pathology, The University of Mississippi Medical Center, Jackson, MS, USA.

3

Department of Epidemiology and Biostatistics, School of Rural and Community Health, The University of Texas Health Science Center at Tyler, Tyler, TX, 75708, USA.

4

Department of Behavioral Health, Child and Adolescent Psychiatry, The University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX, 75708, USA. Richard.Idell@uthct.edu.

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.