C. Bouarab, V. Roullot-Lacarrière, A. Desmedt, P. V. Piazza, J. M. Revest in Mol Psy
Glucocorticoid hormones (GC) have been proposed as one of the biological systems involved in the transition from adaptive to pathological PTSD-like fear memory. In this collaborative paper with Aline Desmedt’s team, we have shown that the deregulation in the hippocampus of the GR-tPA-BDNF-TrkB-Erk1/2MAPK-Egr-1-Synapsin-I (GMES) signaling cascade via the increase of type-1 Plasminogen Activator Inhibitor (PAI-1), induced by intense or traumatic stress and GC, is responsible for the formation of a pathological memory modeling important aspects of PTSD. We have shown that pharmacological inhibition of PAI-1 activity prevented PTSD-like memory formation.
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.
PAI-1 protein is a key molecular effector in the transition from normal to PTSD-like fear memory. *Bouarab C, *Roullot-Lacarrière V, Vallée M, Le Roux A, Guette C, Mennesson M, Marighetto A, *Desmedt A, *Piazza PV, *Revest JM. Mol Psychiatry. 2021 Jan 28.
DOI: 10.1038/s41380-021-01024-1 Online ahead of print. PMID: 33510345.