Abstract
BackgroundIn our previous researches, we have found that apoptosis was induced in the medial prefrontal cortex (mPFC) of post-traumatic stress disorder (PTSD) rats. Endoplasmic reticulum (ER) stress-induced apoptosis has been implicated in the development of several disorder diseases. The aim of this study was to investigate whether endoplasmic reticulum-related pathway is involved in single-prolonged stress (SPS) induced apoptosis in the mPFC of PTSD rats by examining the expression levels of ATF6 alpha (ATF6α), two important downstream molecular chaperones of ATF6α in the ER stress: Glucose-regulated protein (GRP) 78 and ERP57, and apoptotic factors caspase 12, caspase 9, and caspase 3.ResultsOur results of Morris Water Maze (MWM) test showed that after SPS exposure, a striking increase of the escape latency was observed in SPS rats at day 1 through day 6, and SPS rats had much less time spent in target quadrant compared to control rats ( P < 0.01). And From immunofluorescence assays, we found that there was a gradual increase on the protein expression of ATF6α in response to SPS, which indicated ATF6α was activated by SPS. And additionally, immunohistochemistry assays, western blotting and reverse transcription-polymerase chain reaction (RT-PCR) showed that the immunoreactivity, protein and mRNA expression of GRP78 and ERP57 increased on 1, 4 days, and peaked on 7 days after SPS exposure, which revealed that SPS triggered inductions of GRP78 and ERP57 in the mPFC neurons. Moreover, RT-PCR assays demonstrated that there were up-regulations in the transcripts levels of caspase 12, caspase 9, and caspase 3 in response to SPS, which were according with the proteins changes of these apoptotic factors and indicated that ER stress and the activation of caspases contributed to SPS.ConclusionCurrent data in this study highlight that SPS induced ATF6α-dependent Endoplasmic reticulum stress and ER-related apoptosis in the mPFC neurons, which indicated that the endoplasmic reticulum pathway may be involved in PTSD-induced apoptosis.
Highlights
In our previous researches, we have found that apoptosis was induced in the medial prefrontal cortex of post-traumatic stress disorder (PTSD) rats
When the platform was removed from the pool at day 7 for spatial memory testing, a significant effect was observed across the two groups, the results showed that single-prolonged stress (SPS) rats had much less time spent in target quadrant compared to the control rats (Figure 1B), and revealed that SPS model was successfully copied, which had provided guarantee for subsequent studies
To see the changes in cellular agents related to Endoplasmic reticulum (ER) stress and apoptosis, tissue extracted from the medial prefrontal cortex (mPFC) were detected by reverse transcription-polymerase chain reaction (RT-PCR), and the results showed that the mRNA level of the executor of ER
Summary
We have found that apoptosis was induced in the medial prefrontal cortex (mPFC) of post-traumatic stress disorder (PTSD) rats. The aim of this study was to investigate whether endoplasmic reticulum-related pathway is involved in single-prolonged stress (SPS) induced apoptosis in the mPFC of PTSD rats by examining the expression levels of ATF6 alpha (ATF6α), two important downstream molecular chaperones of ATF6α in the ER stress: Glucose-regulated protein (GRP) 78 and ERP57, and apoptotic factors caspase 12, caspase 9, and caspase 3. Over the past several years, neuroimaging studies of PTSD have reported less activation or even deactivation in the medial prefrontal cortex (mPFC) regions during traumatic script-driven imagery in PTSD [6,7,8], and emerging studies showed that PTSD patients had a smaller mPFC [9] All these reports have been implicated that less activation of mPFC is associated with the pathogenesis of PTSD, and has played a key role in this disorder. ER stress triggers the adaptative pathway, unfolding protein response (UPR) [14,15], which is essentially carried out by utilizing three types of ER stress sensor proteins, PERK (double stranded RNAactivated protein kinase-like ER kinase) [16], IRE1α (inositol requiring kinase 1α) [17], and ATF6α (activating transcription factor 6α) [18], and results in the upregulation of ER-derived chaperones and protein-folding enzymes leading the misfolded proteins undergoing the process of degeneration, such as an increase of glucose-related protein (GRP) family, such as GRP78/Bip, and the protein disulfide isomerase (PDI) family, such as ERP57/GRP58 [19,20]
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