Papel de mTOR, BDNF, AMPAR E NMDAR na reconsolidação da memória de extinção

Abstract

Memory reactivation can induce two apparently competing processes, namely extinction and reconsolidation. Extinction involves reduction of a previously acquired response to a stimulus through formation of a new memory trace. On the other hand, reconsolidation involves modification of a previously established memory trace, either for its strengthening or updating. Several studies discuss the opposition between extinction and reconsolidation, but little attention was given to a possible interaction between them. Previous work by our group has demonstrated that extinction memory is susceptible to reconsolidation in a BDNF-dependent manner. In the present work, we investigated the mechanisms involved in activation/expression of BDNF and the pathways it activates in CA1 region of dorsal hippocampus. We trained male Wistar rats in step-down inhibitory avoidance task, extinguished the aversive memory and performed pharmacological interventions before (Ro 25-6981) and/or after (rapamycin, BDNF, anti-BDNF, anisomycin, AP5, pep2m, Ro 25-6981, TCN-201) memory reactivation. In addition, we analyzed expression and phosphorylation of target molecules at different times after reactivation of extinction memory. As a result, we observed that rapamycin administration immediately, but not 6 h after reactivation, impairs reconsolidation of fear extinction, an effect reverted by BDNF co-infusion. In addition, we showed AMPARs trafficking is required for reconsolidation of fear extinction and BDNF is not able to reverse the amnesic effect of AMPARs trafficking blockade. Finally, we observed that NMDARs containing GluN2B participate in destabilization, while NMDARs containing GluN2A participate in trace restabilization during reconsolidation of fear extinction. Finally, our results suggest the existence of a mTOR-BDNF-AMPAR pathway that would act in the memory restabilization.