Evidence that muscarinic receptor activation destabilizes object memories via a mechanism involving CaMKII and synaptic protein degradation

Recently acquired information is stabilized for storage in long-term memory through the process of consolidation. However, when reactivated, consolidated memories can destabilize, rendering them labile and vulnerable to modification. This necessitates a protein synthesis-dependent process of reconsolidation for re-stabilization. Previously our group has demonstrated that novelty-induced object memory destabilization requires M1 muscarinic cholinergic receptors in perirhinal cortex (PRh) and downstream activation of endoplasmic inositol triphosphate (IP3) receptors and the ubiquitin proteasome system (UPS). Given the role of calcium/calmodulin-dependent protein kinase II (CaMKII) in regulating proteasome activity, we hypothesize that novelty-induced object memory destabilization results from increased proteasome activity, which is stimulated by CaMKII following the mobilization of intra-cellular calcium, in PRh. Accordingly, we demonstrate that novelty-induced object memory destabilization requires CaMKII and results in reduction in synaptic protein, Shank 3, in PRh. This research builds upon current understanding of the neurobiological mechanisms underlying the dynamic storage of long-term memory.