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Molecular Mechanisms of Memory Persistence (MEMORY PERSISTENCE)
Date du début: 1 mai 2014, Date de fin: 30 avr. 2016 PROJET  TERMINÉ 

The identification of the molecular and cellular mechanisms that lead to changes in synaptic strength has been a major focus in memory research over the last decades. These mechanisms have been posited to mediate learning and memory. Although many signaling pathways have been shown to initiate the formation of long-term memory they do not appear to be important once memory has been stored/consolidated. A general assumption in the field has been that memory does not require an active biochemical process to be sustained. This view has been challenged in the last few years by the discovery that the persistent activity of a constitutively active protein kinase, PKMζ, is required for memories to persist. This finding had a profound implication because it indicates that memory persistence requires continuous maintenance. We have found that GluA2-containing AMPA receptors (AMPARs) are critical for the expression and maintenance of long-term memories and that the persistent action of PKMζ keeps these receptors at the postsynaptic density. In this research proposal we will build on this finding to identify the components of the signaling pathways regulating the stabilization and removal of synaptic GluR2-AMPARs, and thus memory persistence. We will focus on the major pathways that regulate the trafficking of AMPARs during synaptic plasticity. We will molecularly manipulate in the expression of proteins that have recently emerged as key regulators of AMPAR trafficking and synaptic GluA2 content during synaptic plasticity. We will also study the effect that blocking the interaction of GluA2 with intracellular trafficking proteins exerts on memory persistence and on the susceptibility of memories to be erased. Finally, we will attempt to determine how GluA2 stability is linked to memory maintenance. The knowledge gained from this project may provide new insights for the development of new therapeutic strategies for memory disorders.