title: AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation.
abstract: Both the formation of long-term memory (LTM) and dendritic spine growth that serves as a physical basis for the long-term storage of information require de novo protein synthesis. Memory formation also critically depends on transcription. Adenosine monophosphate-activated protein kinase (AMPK) is a transcriptional regulator that has emerged as a major energy sensor that maintains cellular energy homeostasis. However, still unknown is its role in memory formation. In the present study, we found that AMPK is primarily expressed in neurons in the hippocampus, and then we demonstrated a time-dependent decrease in AMPK activity and increase in mammalian target of rapamycin complex 1 (mTORC1) activity after contextual fear conditioning in the CA1 but not CA3 area of the dorsal hippocampus. Using pharmacological methods and adenovirus gene transfer to bidirectionally regulate AMPK activity, we found that increasing AMPK activity in the CA1 impaired the formation of long-term fear memory, and decreasing AMPK activity enhanced fear memory formation. These findings were associated with changes in the phosphorylation of AMPK and p70s6 kinase (p70s6k) and expression of BDNF and membrane GluR1 and GluR2 in the CA1. Furthermore, the prior administration of an mTORC1 inhibitor blocked the enhancing effect of AMPK inhibition on fear memory formation, suggesting that this negative regulation of contextual fear memory by AMPK in the CA1 depends on the mTORC1 signaling pathway. Finally, we found that AMPK activity regulated hippocampal spine growth associated with memory formation. In summary, our results indicate that AMPK is a key negative regulator of plasticity and fear memory formation.
authors.affiliation: Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, Beijing, China.|National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.|Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Pharmacy, Medical College, Hunan Normal University, Changsha, China.
authors.forename: Yixiao
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Hematology, Affiliated Hospital of Guiyang Medical University, Guiyang, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Sun
authors.affiliation: National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
authors.forename: Zengbo
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Pharmacology and Toxicology, University of Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, Beijing, China.|National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, Beijing, China.|National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jian
authors.affiliation: National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
authors.forename: Yanxue
authors.initials: Y
authors.lastname: Xue
authors.affiliation: National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Hematology, Affiliated Hospital of Guiyang Medical University, Guiyang, China.
authors.forename: Ji-Shi
authors.initials: JS
authors.lastname: Wang
authors.affiliation: Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, Beijing, China.|National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.|Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005239:Fear; D005786:Gene Expression Regulation / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D018782:Maze Learning / Q000502:physiology; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000235:genetics / Q000378:metabolism; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D014161:Transduction, Genetic
chemical_list: D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D055372:AMP-Activated Protein Kinases; D010751:Phosphopyruvate Hydratase; D020123:Sirolimus