title: IRE1α pathway of endoplasmic reticulum stress induces neuronal apoptosis in the locus coeruleus of rats under single prolonged stress.
abstract: Our previous studies have shown evidence of endoplasmic reticulum (ER) stress-induced apoptosis in the hippocampus and mPFC in an animal model of post- traumatic stress disorder (PTSD). Inositol-requiring enzyme 1α (IRE1α) and its downstream molecule X-box binding protein 1 (XBP1) play key roles in the ER-related apoptosis pathway. Dysregulation of the locus coeruleus (LC) has been reported to contribute to cognitive and/or arousal impairments associated with PTSD. The aim of the present study was to explore the role of IRE1α pathway in neuronal apoptosis in the LC of rat models of PTSD. We used an acute exposure to prolonged stress (single prolonged stress, SPS) to model PTSD in rats and examined the effects related to the IRE1α pathway. Neuronal apoptosis in LC was detected by transmission electron microscopy and TUNEL staining. The results showed that the level of LC neuronal apoptosis was markedly increased after SPS. SPS exposure triggered IRE1α pathway, as evidenced by the increased activity of IRE1α, specific splicing of XBP1, and up-regulated expression of binding immunoglobulin protein/78kDa glucose-regulated protein (BiP/GRP78), and C/EBP-homologous protein (CHOP). Treatment with STF-083010, an IRE1α RNase-specific inhibitor, successfully attenuated the above changes. These results indicate that excessive activation of the ER stress-associated IRE1α pathway is involved in LC neuronal apoptosis induced by SPS exposure; this may be a crucial mechanism of the pathogenesis of PTSD.
authors.affiliation: PTSD Laboratory, Department of Histology and Embryology, Basic Medical Science College, China Medical University, Shenyang, China; Department of Histology and Embryology, Binzhou Medical University, Yantai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: PTSD Laboratory, Department of Histology and Embryology, Basic Medical Science College, China Medical University, Shenyang, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Han
authors.affiliation: PTSD Laboratory, Department of Histology and Embryology, Basic Medical Science College, China Medical University, Shenyang, China. Electronic address: yuxiushi2015@163.com.
authors.forename: Yuxiu
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011897:Random Allocation; D017208:Rats, Wistar; D015398:Signal Transduction; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D000071717:X-Box Binding Protein 1 / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D004722:Endoribonucleases; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D013449:Sulfonamides; D013876:Thiophenes; D051742:Transcription Factor CHOP; D000071717:X-Box Binding Protein 1; C497251:Ddit3 protein, rat; C575026:Ern1 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C556690:STF 083010; C000605545:Xbp1 protein, rat
keywords: Apoptosis; IRE1α; Locus coeruleus; Post-traumatic stress disorder; Single-prolonged stress