Zhao Wei, Han Fang, Shi Yuxiu
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.
PTSD Laboratory, Department of Histology and Embryology, Basic Medical Science College, China Medical University, Shenyang, China.
Prog Neuropsychopharmacol Biol Psychiatry. 2016 Aug 1;69:11-8. doi: 10.1016/j.pnpbp.2016.03.008. Epub 2016 Apr 6.
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.
我们之前的研究已经表明，在创伤后应激障碍（PTSD）动物模型中，海马体和内侧前额叶皮质存在内质网（ER）应激诱导的细胞凋亡证据。肌醇需求酶1α（IRE1α）及其下游分子X盒结合蛋白1（XBP1）在ER相关的细胞凋亡途径中起关键作用。据报道，蓝斑（LC）功能失调会导致与PTSD相关的认知和/或觉醒障碍。本研究的目的是探讨IRE1α途径在PTSD大鼠模型蓝斑神经元凋亡中的作用。我们使用急性暴露于长时间应激（单次长时间应激，SPS）来模拟大鼠的PTSD，并研究与IRE1α途径相关的影响。通过透射电子显微镜和TUNEL染色检测蓝斑中的神经元凋亡。结果显示，SPS后蓝斑神经元凋亡水平显著增加。SPS暴露触发了IRE1α途径，IRE1α活性增加、XBP1的特异性剪接以及结合免疫球蛋白蛋白/78kDa葡萄糖调节蛋白（BiP/GRP78）和C/EBP同源蛋白（CHOP）表达上调均证明了这一点。用IRE1α核糖核酸酶特异性抑制剂STF-083010治疗成功减轻了上述变化。这些结果表明，ER应激相关的IRE1α途径过度激活参与了SPS暴露诱导的蓝斑神经元凋亡；这可能是PTSD发病机制的关键机制。
