However, whether induction of synaptic protein degradation can be utilized to enhance memory destabilization is yet to be tested. It has been reported that inhibition of synaptic protein degradation, through blocking the ubiquitin-proteasome system, prevents memory destabilization ( Lee et al., 2008). However, the initial destabilization step is challenging when memories are formed under extremely stressful conditions, and it would require pharmacological assistance ( Tronson and Taylor, 2007 Pitman, 2011 Besnard et al., 2012). Blocking reconsolidation has been suggested as a tool to weaken traumatic memories in anxiety disorders such as post-traumatic stress disorder (PTSD).
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Retrieval of long-term memories (LTM) can induce a destabilization process that returns them into a labile state, which is followed by a protein synthesis-dependent reconsolidation process that serves to strengthen or update the original memories ( Nader et al., 2000 Besnard et al., 2012 Finnie and Nader, 2012 Inaba et al., 2015 Lee et al., 2017). These data indicate that induction of synaptic protein degradation can enhance both synaptic and memory destabilization upon reactivation and that autophagy inducers have the potential to be used as a therapeutic tool in the treatment of anxiety disorders. Using male rats in an in vivo long-term potentiation reconsolidation model, autophagy induction enhanced synaptic destabilization in an N-methyl-D-aspartate receptor-dependent manner. The latter correlated with AMPAR degradation in the spines of the contextual memory-ensemble cells. Using male mice in a contextual fear reconsolidation model, autophagy induction in the amygdala or in the hippocampus enhanced fear or contextual memory destabilization, respectively. Here, using male mice in an auditory fear reconsolidation model, we showed that autophagy contributes to memory destabilization and its induction can be utilized to enhance erasure of a reconsolidation-resistant auditory fear memory that depended on α-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid receptor (AMPAR) endocytosis. In this study, we investigated whether the induction of synaptic protein degradation through autophagy modulation, a major protein degradation pathway, can enhance memory destabilization upon retrieval and whether it can be utilized to overcome these conditions. However, its applicability is restricted by reconsolidation-resistant conditions that constrain the initial memory destabilization. There is substantial interest in memory reconsolidation as a target for the treatment of anxiety disorders such as post-traumatic stress disorder (PTSD).
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