TY - JOUR
T1 - Autophagy enhances memory erasure through synaptic destabilization
AU - Shehata, Mohammad
AU - Abdou, Kareem
AU - Choko, Kiriko
AU - Matsuo, Mina
AU - Nishizono, Hirofumi
AU - Inokuchi, Kaoru
N1 - Publisher Copyright:
© 2018 the authors.
PY - 2018/4/11
Y1 - 2018/4/11
N2 - 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.
AB - 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.
KW - AMPA receptors
KW - Long-term potentiation
KW - NMDA receptors
KW - Post-traumatic stress disorder
KW - Protein degradation
KW - Reconsolidation
UR - http://www.scopus.com/inward/record.url?scp=85050912668&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.3505-17.2018
DO - 10.1523/JNEUROSCI.3505-17.2018
M3 - 学術論文
C2 - 29555855
AN - SCOPUS:85050912668
SN - 0270-6474
VL - 38
SP - 3809
EP - 3822
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 15
ER -