PAI-1 protein is a key molecular effector in the transition from normal to PTSD-like fear memory

C Bouarab,A Desmedt,M Mennesson,C Guette,V Roullot-Lacarrière,A Le Roux,M Vallée,P V Piazza,A Marighetto,J M Revest

doi:10.1038/s41380-021-01024-1

C Bouarab, A Desmedt + Show 8 more

Open Access

https://doi.org/10.1038/s41380-021-01024-1

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Abstract

Moderate stress increases memory and facilitates adaptation. In contrast, intense stress can induce pathological memories as observed in post-traumatic stress disorders (PTSD). A shift in the balance between the expression of tPA and PAI-1 proteins is responsible for this transition. In conditions of moderate stress, glucocorticoid hormones increase the expression of the tPA protein in the hippocampal brain region which by triggering the Erk1/2MAPK signaling cascade strengthens memory. When stress is particularly intense, very high levels of glucocorticoid hormones then increase the production of PAI-1 protein, which by blocking the activity of tPA induces PTSD-like memories. PAI-1 levels after trauma could be a predictive biomarker of the subsequent appearance of PTSD and pharmacological inhibition of PAI-1 activity a new therapeutic approach to this debilitating condition.

Highlights

Stressful events trigger a set of biological responses which generally increase adaptation to potentially harmful situations
Our previous reports demonstrated that the tPA/plasmin system induced by glucocorticoid hormones (GC)-activated glucocorticoid receptor (GR) is a core effector in the regulation of the pro-BDNF/BDNF balance allowing, through the activation of the TrkB/Erk1/2MAPK signaling cascade, the formation of normal fear memory [26,27,28]
Combining in vitro and ex vivo approaches, GRexpressing cell lines and hippocampal slices, respectively, we identified PAI-1 as a plausible upstream molecular effector activated by increasing amounts of GC

Summary

Introduction

Stressful events trigger a set of biological responses which generally increase adaptation to potentially harmful situations. Overly intense or chronic stress can have deleterious effects leading to several behavioral disorders including substance use disorders, depressive-like and anxiety-like disorders, in particular post-traumatic stress disorder (PTSD) [1,2,3,4]. Memory performances are a prototypical example of this dichotomy between the beneficial and pathological effects of stress [5]. Moderate stress increases the memory of associated events facilitating adaptation to future similar situations [2, 3, 6]. Intense stress can alter memory consolidation leading to pathological conditions such as PTSD [3, 4, 7, 8].

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