PAI-1 Deficiency Produces Antidepressant-Resistant Depressive Phenotype

Plasminogen activator inhibitor-1 (PAI-1) deficiency in mice produces a depressive like phenotype that resists antidepressant treatment, supporting the fact that PAI-1 may be a factor of predisposition to major depressive disorder (MDD), according to a recent article published in Acta Neuropathologica Communications.

Researchers in this study focused on how PAI-1 may be a biomarker for MDD by investigating mechanisms connecting PAI-1 and MDD. Investigators used 10-week-old PAI-1 knockout (PAI-1 -/-) male mice and assessed depression symptoms through a range of behavioral tests. Examples of behavioral phenotype tests include splash test, coat state, sucrose preference test, body weight, actimetry, rotarod, and T-maze. Considering all behaviors, PAI-1 -/- mice displayed 6 depressive-related symptoms, including 2 of the markers of MDD in humans (apathetic and anhedonic behaviors). PAI-1 +/+ mice did not show any symptoms.

Researchers considered 2 different mechanistic hypotheses: monoaminergic hypothesis and neurotrophic hypothesis of MDD. Investigators submitted tissue-type plasminogen activator (tPA -/-) knockout male mice to the same behavioral screening system: tPA -/- mice obtained a score of 3, corresponding to 3 depressive-related symptoms, but did not display any apathetic and anhedonic behaviors.

The levels of neurotrophins in the prefrontal cortex, hippocampus, and hypothalamus in PAI-1 -/- mice did not differ from the levels in PAI-1 +/+ mice. These results suggest that the role of PAI-1 in MDD is independent of the tPA–plasminogen system.

Conversely, there was a significant decrease in levels of serotonin in the prefrontal cortex and dopamine in the raphe and hippocampus of PAI-1 -/- mice (Mann–Whitney U test =0, P =.008), which reveals a strong connection between the monoamine levels in cerebral structures and expression of PAI-1. 

Researchers tested the effect of selective serotonin reuptake inhibitors (escitalopram or fluoxetine) on PAI-1 -/- mice because these antidepressants are ineffective in 30% to 40% of patients with MDD. Data showed that chronic treatment over 35 days is ineffective, regardless of dosage levels (either 15 mg/kg or 30 mg/kg) in either medication. 

Researchers concluded that they have “provided here a new genetic model of depression, the PAI-1 knockout mouse, with strong face and construct validity.” The study shows that the PAI-1 knockout mouse is also “a model of resistance to antidepressants” and “suggests that PAI-1 could be an innovative target for the development of new drugs for MDD.” Further research is suggested to “understand how the signaling cascades downstream of PAI-1 affect the risk [for] vulnerability to depression and engage the mental disorder.”

Reference

Party H, Dujarrier C, Hébert M, et al. Plasminogen activator inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments [published online October 14, 2019]. Acta Neuropathol Commun. doi: 10.1186/s40478-019-0807-2