title: Epigenetic modification of PKMζ rescues aging-related cognitive impairment.
abstract: Cognition is impacted by aging. However, the mechanisms that underlie aging-associated cognitive impairment are unclear. Here we showed that cognitive decline in aged rats was associated with changes in DNA methylation of protein kinase Mζ (PKMζ) in the prelimbic cortex (PrL). PKMζ is a crucial molecule involved in the maintenance of long-term memory. Using different behavioral models, we confirmed that aged rats exhibited cognitive impairment in memory retention test 24 h after training, and overexpression of PKMζ in the PrL rescued cognitive impairment in aged rats. After fear conditioning, the protein levels of PKMζ and the membrane expression of GluR2 increased in the PrL in young and adult rats but not in aged rats, and the levels of methylated PKMζ DNA in the PrL decreased in all age groups, whereas the levels of unmethylated PKMζ DNA increased only in young and adult rats. We also found that environmentally enriched housing reversed the hypermethylation of PKMζ and restored cognitive performance in aged rats. Inactivation of PKMζ prevented the potentiating effects of environmental enrichment on memory retention in aged rats. These results indicated that PKMζ might be a potential target for the treatment of aging-related cognitive impairment, suggesting a potential therapeutic avenue.
authors.affiliation: Institute of Mental Health, Peking University Sixth Hospital, and Key Laboratory of Mental Health, Beijing 100191, China.|National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Institute of Mental Health, Peking University Sixth Hospital, and Key Laboratory of Mental Health, Beijing 100191, China.|National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China.
authors.forename: Shi-Qiu
authors.initials: SQ
authors.lastname: Meng
authors.affiliation: National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China.
authors.forename: Yan-Xue
authors.initials: YX
authors.lastname: Xue
authors.affiliation: National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Institute of Mental Health, Peking University Sixth Hospital, and Key Laboratory of Mental Health, Beijing 100191, China.|National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China.
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Sun
authors.affiliation: Institute of Mental Health, Peking University Sixth Hospital, and Key Laboratory of Mental Health, Beijing 100191, China.|National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China.
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Deng
authors.affiliation: National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China.
authors.forename: Na
authors.initials: N
authors.lastname: Chen
authors.affiliation: National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Bao
authors.affiliation: National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China.
authors.forename: Fei-Long
authors.initials: FL
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Cao
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhu
authors.affiliation: National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.affiliation: Brain Research Centre, Departments of Medicine and Psychiatry, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Song
authors.affiliation: Institute of Mental Health, Peking University Sixth Hospital, and Key Laboratory of Mental Health, Beijing 100191, China.|National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China.|Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000523:psychology*; D000818:Animals; D060825:Cognitive Dysfunction / Q000201:enzymology* / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D007858:Learning / Q000502:physiology; D008297:Male; D057567:Memory, Long-Term / Q000502:physiology; D017397:Prefrontal Cortex / Q000201:enzymology; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011493:Protein Kinase C; C504730:protein kinase M zeta, rat