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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Main Authors: 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
Format: Article
Language:English
Published: BMC 2019-10-01
Series:Acta Neuropathologica Communications
Subjects:
Online Access:http://link.springer.com/article/10.1186/s40478-019-0807-2
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spelling 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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