title: Critical Role of Endoplasmic Reticulum Stress in Chronic Intermittent Hypoxia-Induced Deficits in Synaptic Plasticity and Long-Term Memory.
abstract: OBJECTIVE
  This study examined the role of endoplasmic reticulum (ER) stress in mediating chronic intermittent hypoxia (IH)-induced neurocognitive deficits. We designed experiments to demonstrate that ER stress is initiated in the hippocampus under chronic IH and determined its role in apoptotic cell death, impaired synaptic structure and plasticity, and memory deficits.
  
  
  RESULTS
  Two weeks of IH disrupted ER fine structure and upregulated ER stress markers, glucose-regulated protein 78, caspase-12, and C/EBP homologous protein, in the hippocampus, which could be suppressed by ER stress inhibitors, tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid. Meanwhile, ER stress induced apoptosis via decreased Bcl-2, promoted reactive oxygen species production, and increased malondialdehyde formation and protein carbonyl, as well as suppressed mitochondrial function. These effects were largely prevented by ER stress inhibitors. On the other hand, suppression of oxidative stress could reduce ER stress. In addition, the length of the synaptic active zone and number of mature spines were reduced by IH. Long-term recognition memory and spatial memory were also impaired, which was accompanied by reduced long-term potentiation in the Schaffer collateral pathway. These effects were prevented by coadministration of the TUDCA.
  
  
  CONCLUSIONS
  These results show that ER stress plays a critical role in underlying memory deficits in obstructive sleep apnea (OSA)-associated IH. Attenuators of ER stress may serve as novel adjunct therapeutic agents for ameliorating OSA-induced neurocognitive impairment.
authors.affiliation: 1 Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong , Shatin, Hong Kong, China .
authors.forename: Lin-Hao
authors.initials: LH
authors.lastname: Xu
authors.affiliation: 1 Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong , Shatin, Hong Kong, China .
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.affiliation: 1 Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong , Shatin, Hong Kong, China .
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Shi
authors.affiliation: 1 Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong , Shatin, Hong Kong, China .
authors.forename: Li-Da
authors.initials: LD
authors.lastname: Du
authors.affiliation: 2 Department of Psychiatry, Prince of Wales Hospital , Shatin, Hong Kong, China .
authors.forename: Yun-Kwok
authors.initials: YK
authors.lastname: Wing
authors.affiliation: 3 Department of Pediatrics, Prince of Wales Hospital , Shatin, Hong Kong, China .
authors.forename: Albert M
authors.initials: AM
authors.lastname: Li
authors.affiliation: 1 Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong , Shatin, Hong Kong, China .
authors.forename: Ya
authors.initials: Y
authors.lastname: Ke
authors.affiliation: 1 Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong , Shatin, Hong Kong, China .
authors.forename: Wing-Ho
authors.initials: WH
authors.lastname: Yung
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D008568:Memory; D057567:Memory, Long-Term; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009473:Neuronal Plasticity; D009474:Neurons / Q000187:drug effects; D010654:Phenylbutyrates / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013131:Spine / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology
chemical_list: D010654:Phenylbutyrates; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C075773:4-phenylbutyric acid; D053148:Caspase 3
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