Abstract
There is substantial interest in memory reconsolidation as a target for the treatment of anxiety disorders such as post-traumatic stress disorder (PTSD). However, its applicability is restricted by reconsolidation-resistant boundary conditions that constrain the initial memory destabilization. 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. 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. 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. The latter correlated with AMPAR degradation in the spines of the contextual memory-ensemble cells. 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. 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.
SIGNIFICANCE STATEMENT
It has been reported that inhibiting synaptic protein degradation prevents memory destabilization. However, whether the reverse relation is true and whether it can be utilized to enhance memory destabilization is still unknown. Here we addressed this question on the behavioral, molecular and synaptic levels, and showed that induction of autophagy, a major protein degradation pathway, can enhance memory and synaptic destabilization upon reactivation. We also show that autophagy induction can be utilized to overcome a reconsolidation-resistant memory, suggesting autophagy inducers as a potential therapeutic tool in the treatment of anxiety disorders.
Footnotes
The authors declare no competing financial interests.
This work was supported by the Grant-in-Aid for Scientific Research on Innovative Areas “Memory dynamism” (JP25115002) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), JSPS KAKENHI grant number JP23220009, the Core Research for Evolutional Science and Technology (CREST) program (JPMJCR13W1) of the Japan Science and Technology Agency (JST), the Mitsubishi Foundation, the Uehara Memorial Foundation, and the Takeda Science Foundation support to K.I.; and by a Grant-in-Aid for young scientists from JSPS KAKENHI grant number JP25830007 to M.S. The Otsuka Toshimi Scholarship Foundation supported K.A.
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