O papel da proteína PKMζ na reconsolidação da memória espacial

Abstract

A fundamental requirement of everyday life is to successfully encode and remember the location of objects, landmarks, or places in space. The loss of this capacity is one of the first symptoms of cognitive impairment in Alzheimer's Disease, and it is often investigated in rodents using the Morris water maze (MWM). During training in the MWM, animals use spatial cues to form a spatial representation of the environment and use it to find a submerged platform that serves as an escape. However, if the platform is not found, the animals must re-evaluate their memory and likely modify it through a reconsolidation process. It has been suggested that the hippocampus participates in the reconsolidation of various types of memory through mechanisms involving signaling mediated by PKMζ, an atypical isoform of PKC, which has been implicated in the maintenance of long-term memory. However, the role of this protein in the reconsolidation of spatial memory is not yet understood. This study investigated the involvement of PKMζ in the reconsolidation of spatial memory in male Wistar rats. We observed that intra-hippocampal infusion of ZIP, a PKMζ inhibitor peptide, or antisense oligonucleotide for PKMζ, immediately after a test in the absence of an escape platform, prevents the persistence of spatial memory. The amnesic effect promoted by ZIP is blocked by pre-test administration of the NMDA-GluN2B receptor antagonist, RO25-6981, and by proteasome inhibition. We also found that the amnesia promoted by ZIP is mimicked by inhibition of AMPA receptor insertion into the synapse and reversed by co-infusion of a blocker of receptor internalization. These findings suggest that hippocampal PKMζ is essential for the persistence of spatial preference after its unreinforced reactivation, within a narrow time window, and that this effect may be mediated via modulation of AMPA receptor activity.