Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments
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 mo...
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Online Access: | http://link.springer.com/article/10.1186/s40478-019-0807-2 |
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doaj-f491f63c017d42d194af67d6b45837702020-11-25T03:56:37ZengBMCActa Neuropathologica Communications2051-59602019-10-017111210.1186/s40478-019-0807-2Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatmentsHélène Party0Cléo Dujarrier1Marie Hébert2Sophie Lenoir3Sara Martinez de Lizarrondo4Raphaël Delépée5Claudine Fauchon6Marie-Christine Bouton7Pauline Obiang8Olivier Godefroy9Etienne Save10Laurent Lecardeur11Joëlle Chabry12Denis Vivien13Véronique Agin14UNICAEN, INSERM, INSERM UMR-S 1237, Physiopathology and Imaging of Neurological Disorders, Normandie UniversityUNICAEN, INSERM, INSERM UMR-S 1237, Physiopathology and Imaging of Neurological Disorders, Normandie UniversityUniversity of Trento, Center for Mind/Brain ScienceUNICAEN, INSERM, INSERM UMR-S 1237, Physiopathology and Imaging of Neurological Disorders, Normandie UniversityUNICAEN, INSERM, INSERM UMR-S 1237, Physiopathology and Imaging of Neurological Disorders, Normandie UniversityUNICAEN, PRISMM core facility, SF4206 ICORE, Comprehensive Cancer Center F. Baclesse, Normandie UniversityUNICAEN, Centre Universitaire de Ressources Biologiques (CURB), Normandie UniversityINSERM UMR-S U1148, Laboratory for Vascular and Translational Science, Paris Diderot University, Sorbonne Paris Cité UniversityUNICAEN, INSERM, INSERM UMR-S 1237, Physiopathology and Imaging of Neurological Disorders, Normandie UniversityDepartment of Neurology and Laboratory of Functional Neurosciences, EA 4559, Amiens University HospitalCNRS, LNC, Laboratory of Cognitive Neuroscience UMR 7291, Aix Marseille UniversityUNICAEN, EA 7466, Imagery and Therapeutic Strategy in Schizophrenia, Normandie UniversityInstitut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS-Université Côte d’Azur, Sophia AntipolisUNICAEN, INSERM, INSERM UMR-S 1237, Physiopathology and Imaging of Neurological Disorders, Normandie UniversityUNICAEN, INSERM, INSERM UMR-S 1237, Physiopathology and Imaging of Neurological Disorders, Normandie UniversityAbstract 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.http://link.springer.com/article/10.1186/s40478-019-0807-2Major depressive disorderPlasminogen activator Inhibitor-1SerotoninDopamineEscitalopramFluoxetine |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hélène Party Cléo Dujarrier Marie Hébert Sophie Lenoir Sara Martinez de Lizarrondo Raphaël Delépée Claudine Fauchon Marie-Christine Bouton Pauline Obiang Olivier Godefroy Etienne Save Laurent Lecardeur Joëlle Chabry Denis Vivien Véronique Agin |
spellingShingle |
Hélène Party Cléo Dujarrier Marie Hébert Sophie Lenoir Sara Martinez de Lizarrondo Raphaël Delépée Claudine Fauchon Marie-Christine Bouton Pauline Obiang Olivier Godefroy Etienne Save Laurent Lecardeur Joëlle Chabry Denis Vivien Véronique Agin Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments Acta Neuropathologica Communications Major depressive disorder Plasminogen activator Inhibitor-1 Serotonin Dopamine Escitalopram Fluoxetine |
author_facet |
Hélène Party Cléo Dujarrier Marie Hébert Sophie Lenoir Sara Martinez de Lizarrondo Raphaël Delépée Claudine Fauchon Marie-Christine Bouton Pauline Obiang Olivier Godefroy Etienne Save Laurent Lecardeur Joëlle Chabry Denis Vivien Véronique Agin |
author_sort |
Hélène Party |
title |
Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments |
title_short |
Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments |
title_full |
Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments |
title_fullStr |
Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments |
title_full_unstemmed |
Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments |
title_sort |
plasminogen activator inhibitor-1 (pai-1) deficiency predisposes to depression and resistance to treatments |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2019-10-01 |
description |
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. |
topic |
Major depressive disorder Plasminogen activator Inhibitor-1 Serotonin Dopamine Escitalopram Fluoxetine |
url |
http://link.springer.com/article/10.1186/s40478-019-0807-2 |
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