Abstract
Major depressive disorder (MDD) is one of the most frequent psychiatric illnesses, leading to reduced quality of life, ability to work and sociability, thus ranking among the major causes of disability and morbidity worldwide. To date, genetic and environmental determinants of MDD remain mostly unknown. Here, we investigated whether and how the Plasminogen Activator Inhibitor-1 (PAI-1) may contribute to MDD. We first examined the phenotype of PAI-1 knockout (PAI-1−/−) and wild-type (PAI-1+/+) male mice with a range of behavioral tests assessing depressive-like behaviors (n = 276). We next investigated the mechanisms relating PAI-1 to MDD using molecular, biochemical and pharmacological analyzes. We demonstrate here that PAI-1 plays a key role in depression by a mechanism independent of the tissue-type Plasminogen Activator (tPA) – Brain-Derived Neurotrophic Factor (BDNF) axis, but associated with impaired metabolisms of serotonin and dopamine. Our data also reveal that PAI-1 interferes with therapeutic responses to selective serotonin reuptake inhibitors (escitalopram, fluoxetine). We thus highlight a new genetic preclinical model of depression, with the lack of PAI-1 as a factor of predisposition to MDD. Altogether, these original data reveal that PAI-1 should be now considered as a key player of MDD and as a potential target for the development of new drugs to cure depressive patients resistant to current treatments.
Highlights
Major depressive disorder (MDD) is one of the most frequent psychiatric illnesses, leading to reduced quality of life, ability to work and sociability, ranking among the major causes of disability and morbidity worldwide [19, 40, 50]
The depressive-like phenotype of Plasminogen Activator Inhibitor-1 (PAI-1)−/− mice is independent of the type Plasminogen Activator (tPA)-Brain-Derived Neurotrophic Factor (BDNF) axis To determine whether the involvement of PAI-1 in depression was associated, or not, with its interaction with tPA, we examined the behavioral phenotype of tPA −/− mice and that of their wild-type littermates with our depression screening system
In accordance with the monoamine hypothesis of depression, we demonstrate that these phenotypic characteristics are associated with changes in monoamine levels in brain structures known to be involved in MDD
Summary
Major depressive disorder (MDD) is one of the most frequent psychiatric illnesses, leading to reduced quality of life, ability to work and sociability, ranking among the major causes of disability and morbidity worldwide [19, 40, 50]. Several clinical studies have reported increased levels of plasmatic PAI-1 in depressed patients [14, 22, 24, 32] Convergent with these findings, Tsai et al [48] demonstrated that the genetic variants of SERPINE1 gene (coding PAI-1) in humans may increase MDD susceptibility and decrease the acute therapeutic response to SSRIs. At the preclinical scale, increased concentrations of cerebral PAI-1 have been found in rats exposed to a chronic unpredicted mild stress (CUMS) procedure [45]. At the preclinical scale, increased concentrations of cerebral PAI-1 have been found in rats exposed to a chronic unpredicted mild stress (CUMS) procedure [45] All together, these studies suggest that PAI-1 could be a biomarker of depression, its direct and precise implication in MDD pathogenesis has not been demonstrated
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