| Resumo: |
Ageing is characterized by the decline of organic and cognitive functions, and among them, of memory. While some memories are ephemeral and last only for few moments, others remain deeply rooted during a lifetime. The mechanisms underlying memory consolidation have been relatively well explored. However, the molecular mechanisms underlying the persistence of long-term memory storage remain elusive. Protein kinase M ζ (PKMζ) is a persistently active, and its autonomous activity underlies the maintenance of long-term potentiation (LTP), a cellular model of learning and memory, and also the storage of different types of memory. PKMζ exerts its actions by inhibiting the endocytosis of GluA2-containing α-amino-3-hydroxy-methyl-5-4-isoxazolepropionic acid (AMPA) receptors. Contextual fear conditioning (CFC) memory is a form of learning with high adaptive value due to its importance for survival, and because of that, is characterized by prolonged retention. This memory recruits many neuronal circuits, among them the prelimbic cortex (PrL). In order to characterize the molecular mechanisms underlying CFC memory persistence, this study aims to investigate the involvement, in this process, of PKMζ and GluA2-containing AMPA receptors, as well as their interaction, in the PrL, utilizing a rodent experimental model. For this purpose, we trained rats in a CFC paradigm and administered in the PrL infusions of ZIP (Zeta Inhibitory Peptide, 10 nmol per side), a PKMζ inhibitor, GluA23Y (100 pmol per side), a GluA2-dependent AMPA receptor endocytosis inhibitor or GluA23Y(s), a scrambled control peptide, two or twenty days after conditioning, and evaluated long-term memory retention twenty-four hours later. We verified that infusion of GluA23Y or GluA23Y(s) did not affect the maintenance of recent or remote CFC memory. Besides that, PKMζ inhibition in the PrL did not impair the maintenance of recent CFC memory. However, PKMζ inhibition twenty days after training impaired remote CFC memory retention. This impairment was prevented by the infusion of GluA23Y, but not of GluA23Y(s). These results suggest that PKMζ is not required in the PrL for the maintenance of recent CFC memory. Also, acute inhibition of GluA2-containing AMPA receptor endocytosis does not affect recent or remote CFC memory maintenance. However, PKMζ is essential to ensure the maintenance of remote CFC memory, and it does so by preventing prelimbic GluA2-dependent AMPA receptor internalization. This work confirms a 11 crucial role for PrL in fear memory and also contributes for the understanding of the molecular mechanisms underlying memory persistence. |
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