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Autophagy enhances memory erasure through synaptic destabilization

Shehata, Mohammad and Abdou, Kareem and Choko, Kiriko and Matsuo, Mina and Nishizono, Hirofumi and Inokuchi, Kaoru (2018) Autophagy enhances memory erasure through synaptic destabilization. Journal of Neuroscience, 38 (15). pp. 3809-3822. ISSN 0270-6474. PMCID PMC6705918. doi:10.1523/JNEUROSCI.3505-17.2018.

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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.

Item Type:Article
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URLURL TypeDescription CentralArticle Paper
Shehata, Mohammad0000-0003-1710-3009
Abdou, Kareem0000-0002-1033-1650
Inokuchi, Kaoru0000-0002-5393-3133
Alternate Title:Autophagy enhances memory destabilization
Additional Information:© 2018 the authors. For the first six months after publication SfN’s license will be exclusive. Beginning six months after publication the Work will be made freely available to the public on SfN’s website to copy, distribute, or display under a Creative Commons Attribution 4.0 International (CC BY 4.0) license ( Received: 10 December 2017; Revised: 14 February 2018; Accepted: 21 February 2018; Published: 19 March 2018. The authors declare no competing financial interests. This work was supported by Ministry of Education, Culture, Sports, Science, and Technology Grant-in-Aid for Scientific Research on Innovative Areas “Memory dynamism” JP25115002, Japan Society for the Promotion of Science KAKENHI Grant JP23220009, Japan Science and Technology Agency Core Research for Evolutional Science and Technology Program JPMJCR13W1, the Mitsubishi Foundation, and the Uehara Memorial Foundation. K.I. was supported by the Takeda Science Foundation. M.S. was supported by Japan Society for the Promotion of Science KAKENHI Grant-in-Aid for Young Scientists JP25830007. K.A. was supported by the Otsuka Toshimi Scholarship Foundation. We thank Noriaki Ohkawa for assistance with c-fos-tTA mice; Reiko Okubo-Suzuki and Yoshito Saitoh for assistance with electrophysiology; Sakurako Kosugi for lentivirus preparation; and Shuhei Tsujimura for maintenance of mice.
Funding AgencyGrant Number
Ministry of Education, Culture, Sports, Science and Technology (MEXT)JP25115002
Ministry of Education, Culture, Sports, Science and Technology (MEXT)JP23220009
Japan Science and Technology AgencyJPMJCR13W1
Mitsubishi FoundationUNSPECIFIED
Uehara Memorial FoundationUNSPECIFIED
Takeda Science FoundationUNSPECIFIED
Japan Society for the Promotion of Science (JSPS)JP25830007
Otsuka Toshimi Scholarship FoundationUNSPECIFIED
Subject Keywords:AMPA receptors; long-term potentiation; NMDA receptors; post-traumatic stress disorder; protein degradation; reconsolidation
Issue or Number:15
PubMed Central ID:PMC6705918
Record Number:CaltechAUTHORS:20180320-104134226
Persistent URL:
Official Citation:Autophagy Enhances Memory Erasure through Synaptic Destabilization Mohammad Shehata, Kareem Abdou, Kiriko Choko, Mina Matsuo, Hirofumi Nishizono, Kaoru Inokuchi Journal of Neuroscience 11 April 2018, 38 (15) 3809-3822; DOI: 10.1523/JNEUROSCI.3505-17.2018
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:85378
Deposited By: Tony Diaz
Deposited On:26 Mar 2018 22:16
Last Modified:04 Mar 2022 16:57

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