title: Chronic copper exposure causes spatial memory impairment, selective loss of hippocampal synaptic proteins, and activation of PKR/eIF2α pathway in mice.
abstract: Copper is an essential element for human growth and development; however, excessive intake of copper could contribute to neurotoxicity. Here we show that chronic exposure to copper in drinking water impaired spatial memory with simultaneous selective loss of hippocampal pre-synaptic protein synapsin 1, and post-synaptic density protein (PSD)-93/95 in mice. Copper exposure was shown to elevate the levels of nitrotyrosine and 8-hydroxydeoxyguanosine (8-OHdG) in hippocampus, two markers of oxidative stress. Concurrently, we also found that copper exposure activated double stranded RNA-dependent protein kinase (PKR) as evidenced by increased ratio of phosphorylated PKR at Thr451 and total PKR and increased the phosphorylation of its downstream signaling molecule eukaryotic initiation factor 2α (eIF2α) at Ser51 in hippocampus. Consistent with activation of PKR/eIF2α signaling pathway which was shown to mediate synaptic deficit and cognitive impairment, the levels of activating transcription factor 4 (ATF-4), a downstream signaling molecule of eIF2α and a repressor of CREB-mediated gene expression, were significantly increased, while the activity of cAMP response elements binding protein (CREB) was inactivated as suggested by decreased phosphorylation of CREB at Ser133 by copper exposure. In addition, the expression of the pro-apoptotic target molecule C/EBP homology protein (CHOP) of ATF-4 was upregulated and hippocampal neuronal apoptosis was induced by copper exposure. Taken together, we propose that chronic copper exposure might cause spatial memory impairment, selective loss of synaptic proteins, and neuronal apoptosis through the mechanisms involving activation of PKR/eIF2α signaling pathway.
authors.affiliation: Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China College of Life Sciences, Shenzhen University, Shenzhen, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Ma
authors.affiliation: College of Life Sciences, Shenzhen University, Shenzhen, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Ying
authors.affiliation: Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Sui
authors.affiliation: Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Huang
authors.affiliation: Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Linqing
authors.initials: L
authors.lastname: Yang
authors.affiliation: Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Huang
authors.affiliation: Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
authors.forename: Xifei
authors.initials: X
authors.lastname: Yang
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002908:Chronic Disease; D019327:Copper Sulfate / Q000633:toxicity*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008569:Memory Disorders / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology; D016704:Synapsins / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: C081452:Atf4 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C103652:Elf2 protein, mouse; D008565:Membrane Proteins; D016704:Synapsins; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C002744:3-nitrotyrosine; D014443:Tyrosine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D019892:eIF-2 Kinase; C501445:Dlg2 protein, mouse; D051528:Guanylate Kinases; D003849:Deoxyguanosine; D019327:Copper Sulfate
keywords: Copper; double stranded RNA-dependent protein kinase (PKR); eukaryotic initiation factor 2α (eIF2α); spatial learning and memory; synaptic proteins