Influence of early stress on memory reconsolidation: Implications for post-traumatic stress disorder treatment.

Post-traumatic stress disorder (PTSD) is a common consequence of exposure to a life-threatening event. Currently, pharmacological treatments are limited by high rates of relapse, and novel treatment approaches are needed. We have recently demonstrated that propranolol, a ß-adrenergic antagonist, inhibited aversive memory reconsolidation in animals. Following this, in an open-label study 70% of patients with PTSD treated with propranolol during reactivation of traumatic memory exhibited full remission. However, the reason why 30% of these patients did not respond positively to propranolol treatment is still unclear. One of the major candidates as factor of treatment resistance is the patient's early-life traumatic history. To test the role of this factor, mice with pre- or postnatal stress are being tested in fear conditioning and in a new behavioral task, the "city-like", specifically designed as a mouse model of PTSD. After reactivation of the traumatic event, mice received propranolol injection to block the noradrenergic system during memory reconsolidation. Results show that, in the "city-like" test, control mice strongly avoided the shock compartment but also the compartments containing cues associated with the electric shocks. Injection of propranolol after reactivation greatly reduced the memory of the traumatic event, but this effect was not present when mice had received pre- or postnatal stress. Moreover, propranolol produced only a very weak effect in the fear conditioning test, and never changed the corticosterone level whatever the behavioral experiment. Taken together our results suggest that our new behavioural paradigm is well adapted to PTSD study in mice, and that early stress exposure may have an impact on propranolol PTSD treatment outcome. These data are critical to understanding the effect of propranolol treatment, in order to improve the therapeutic protocol currently used in humans.