TY - JOUR
T1 - Autophagy coupled to translation is required for long-term memory
AU - Pandey, Kiran
AU - Yu, Xiao Wen
AU - Steinmetz, Adam
AU - Alberini, Cristina M.
N1 - Funding Information:
We thank Prof. Claudio Hetz (Institute of Biomedical Sciences, University of Chile) for generously providing the pAAV-mCherry-GFP-LC3B plasmid. We thank Dr. Theresa Swayne at the Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University (supported by NIH grant P30 CA013696) for providing image processing scripts and protocols. We thank Gabriella Pollonini for technical support. The studies presented in this manuscript were supported by the NIH grant MH065635 to CMA.
Funding Information:
This work was supported by the National Institute of Mental Health [MH065635]. We thank Prof. Claudio Hetz (Institute of Biomedical Sciences, University of Chile) for generously providing the pAAV-mCherry-GFP-LC3B plasmid. We thank Dr. Theresa Swayne at the Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University (supported by NIH grant P30 CA013696) for providing image processing scripts and protocols. We thank Gabriella Pollonini for technical support. The studies presented in this manuscript were supported by the NIH grant MH065635 to CMA.
Publisher Copyright:
© 2020 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2021
Y1 - 2021
N2 - An increase in protein synthesis following learning is a fundamental and evolutionarily conserved mechanism of long-term memory. To maintain homeostasis, this protein synthesis must be counterbalanced by mechanisms such as protein degradation. Recent studies reported that macroautophagy/autophagy, a major protein degradation mechanism, is required for long-term memory formation. However, how learning regulates autophagy and recruits it into long-term memory formation remains to be established. Here, we show that inhibitory avoidance in rats significantly increases the levels of autophagy and lysosomal degradation proteins, including BECN1/beclin 1, LC3-II, SQSTM1/p62 and LAMP1, as well as autophagic flux in the hippocampus. Moreover, pharmacological inhibition or targeted molecular disruption of the learning-induced autophagy impairs long-term memory, leaving short-term memory intact. The increase in autophagy proteins results from active translation of their mRNA and not from changes in their total mRNA levels. Additionally, the induction of autophagy requires the immediate early gene Arc/Arg3.1. Finally, in contrast to classical regulation of autophagy in other systems, we found that the increase in autophagy upon learning is dispensable for the increase in protein synthesis. We conclude that coupling between learning-induced translation and autophagy, rather than translation per se, is an essential mechanism of long-term memory. Abbreviations: AAV: adeno-associated virus; ARC/ARG3.1: activity regulated cytoskeletal-associated protein; ATG: autophagy related; DG: dentate gyrus; GFP: green fluorescent protein; IA: inhibitory avoidance; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; ODN: oligodeoxynucleotide; qPCR: quantitative polymerase chain reaction; SBI: SBI0206965; SQSTM1/p62: sequestosome 1; SUnSET: surface sensing of translation; TRAP: translating ribosome affinity purification; ULK1: unc-51 like kinase 1.
AB - An increase in protein synthesis following learning is a fundamental and evolutionarily conserved mechanism of long-term memory. To maintain homeostasis, this protein synthesis must be counterbalanced by mechanisms such as protein degradation. Recent studies reported that macroautophagy/autophagy, a major protein degradation mechanism, is required for long-term memory formation. However, how learning regulates autophagy and recruits it into long-term memory formation remains to be established. Here, we show that inhibitory avoidance in rats significantly increases the levels of autophagy and lysosomal degradation proteins, including BECN1/beclin 1, LC3-II, SQSTM1/p62 and LAMP1, as well as autophagic flux in the hippocampus. Moreover, pharmacological inhibition or targeted molecular disruption of the learning-induced autophagy impairs long-term memory, leaving short-term memory intact. The increase in autophagy proteins results from active translation of their mRNA and not from changes in their total mRNA levels. Additionally, the induction of autophagy requires the immediate early gene Arc/Arg3.1. Finally, in contrast to classical regulation of autophagy in other systems, we found that the increase in autophagy upon learning is dispensable for the increase in protein synthesis. We conclude that coupling between learning-induced translation and autophagy, rather than translation per se, is an essential mechanism of long-term memory. Abbreviations: AAV: adeno-associated virus; ARC/ARG3.1: activity regulated cytoskeletal-associated protein; ATG: autophagy related; DG: dentate gyrus; GFP: green fluorescent protein; IA: inhibitory avoidance; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; ODN: oligodeoxynucleotide; qPCR: quantitative polymerase chain reaction; SBI: SBI0206965; SQSTM1/p62: sequestosome 1; SUnSET: surface sensing of translation; TRAP: translating ribosome affinity purification; ULK1: unc-51 like kinase 1.
KW - Arc/Arg3.1
KW - autophagic flux
KW - autophagy
KW - memory
KW - translating ribosome affinity purification
KW - translation
UR - http://www.scopus.com/inward/record.url?scp=85087016832&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087016832&partnerID=8YFLogxK
U2 - 10.1080/15548627.2020.1775393
DO - 10.1080/15548627.2020.1775393
M3 - Article
C2 - 32501746
AN - SCOPUS:85087016832
SN - 1554-8627
VL - 17
SP - 1614
EP - 1635
JO - Autophagy
JF - Autophagy
IS - 7
ER -