Autophagy enhances memory erasure through synaptic destabilization

Mohammad Shehata, Kareem Abdou, Kiriko Choko, Mina Matsuo, Hirofumi Nishizono, Kaoru Inokuchi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

There is substantial interest in memory reconsolidation as a target for the treatment of anxiety disorders, such as post-traumatic stress disorder. 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 used 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 used to enhance erasure of a reconsolidation-resistant auditory fear memory that depended on 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 LTP reconsolidation model, autophagy induction enhanced synaptic destabilization in an NMDAR-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.

Original languageEnglish
Pages (from-to)3809-3822
Number of pages14
JournalJournal of Neuroscience
Volume38
Issue number15
DOIs
StatePublished - 2018/04/11

Keywords

  • AMPA receptors
  • Long-term potentiation
  • NMDA receptors
  • Post-traumatic stress disorder
  • Protein degradation
  • Reconsolidation

ASJC Scopus subject areas

  • General Neuroscience

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