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Changes in the Glucocorticoid Receptor and Ca2+/Calreticulin-Dependent Signalling Pathway in the Medial Prefrontal Cortex of Rats with Post-traumatic Stress Disorder

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Abstract

The glucocorticoid receptor (GR), calreticulin (CRT) and protein kinase C (PKC) have all been implicated in the Ca2+-dependent signalling pathway, which plays an important role in the plasticity of the central nervous system, learning and memory. The medial prefrontal cortex (mPFC) is known to be involved in mechanisms of learning and memory. In the present study, single prolonged stress (SPS) was used as an animal model of post-traumatic stress disorder (PTSD). The Morris water maze test was used to detect rats’ ability for spatial memory and learning. A fluorescence spectrophotometer was used to measure the concentration of intracellular Ca2+ in mPFC. Immunohistochemistry, immunofluorescence, western blot and reverse transcription polymerase chain reaction were used to explore changes in GR, CRT and PKC in mPFC of SPS rats. The concentration of Ca2+ in mPFC was increased in the SPS rats. We found increased intensity of GR and CRT immunoreactivity and increased messenger RNA (mRNA) levels of GR, CRT and PKC in mPFC of the SPS groups, although the degree and time of increase was different among them. The protein levels of cytoplasmic GR, cytoplasmic CRT and cytoplasmic pPKC increased in mPFC of the SPS groups, whereas the protein level of nuclear GR decreased in comparison with the control group. As a conclusion, changed CRT and GR/PKC were involved in the mechanism of SPS-induced dysfunctional mPFC.

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References

  • Allan AM, Goggin SL, Kevin K, Caldwell KK et al (2014) Prenatal alcohol exposure modifies glucocorticoid receptor subcellular distribution in the medial prefrontal cortex and impairs frontal cortex-dependent learning. PLoS ONE 9(4):e96200

    Article  PubMed Central  PubMed  Google Scholar 

  • American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th edn. American Psychiatric Association, Washington

    Book  Google Scholar 

  • Bremner JD (2007) Neuroimaging in posttraumatic stress disorder and other stress related disorder. Neuroimaging Clin N Am 17(4):523–538

    Article  PubMed Central  PubMed  Google Scholar 

  • Brewin CR, Andrews B, Valentine JD (2000) Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. J Consult Clin Psychol 68(5):748–766

    Article  CAS  PubMed  Google Scholar 

  • Cristina Castañeda-Patlán M, Razo-Paredes R, Carrisoza-Gaytán R et al (2010) Protein kinase C is involved in the regulation of several calreticulin posttranslational modifications. Int J Biochem Cell Biol 42(1):120–131

    Article  PubMed  Google Scholar 

  • De Bock M, Decrock E, Wang N et al (2014) The dual face of connexin-based astroglial Ca2+ communication: a key player in brain physiology and a prime target in pathology. Biochim Biophys Acta 1843(10):2211–2232

    Article  PubMed  Google Scholar 

  • Donnelly S, Roake W, Brown S et al (2006) Impaired recognition of apoptotic neutrophils by the C1q/calreticulin and CD91 pathway in systemic lupus erythematosus. Arthritis Rheum 54:1543–1556

    Article  CAS  PubMed  Google Scholar 

  • Gao W, Xu H, Liang M et al (2013) Association between reduced expression of hippocampal glucocorticoid receptors and cognitive dysfunction in a rat model of traumatic brain injury due to lateral head acceleration. Neurosci Lett 533:50–54

    Article  CAS  PubMed  Google Scholar 

  • Han F, Yan S, Shi Y (2013) Single-prolonged stress induces endoplasmic reticulum-dependent apoptosis in the hippocampus in a rat model of post-traumatic stress disorder. PLoS ONE 8(7):e69340

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hristov KL, Smith AC, Parajuli SP et al (2014) Large-conductance voltage-and Ca2+-activated K+ channel regulation by protein kinase C in guinea pig urinary bladder smooth muscle. Am J Physiol Cell Physiol 306(5):C460–C470

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hsu TC, Bodine PV, Litwack G (1991) Endogenous modulators of glucocorticoid receptor function also regulate purified protein kinase C. J Biol Chem 266(26):17573–17579

    CAS  PubMed  Google Scholar 

  • Knox D, Nault T, Henderson C et al (2012) Glucocorticoid receptors and extinction retention deficits in the single prolonged stress model. Neuroscience 223:163–173

    Article  CAS  PubMed  Google Scholar 

  • Lee D, Singaravelu G, Park BJ et al (2007) Differential requirement of unfolded protein response pathway for calreticulin expression in Caenorhabditis elegans. J Mol Biol 372(2):331–340

    Article  CAS  PubMed  Google Scholar 

  • Li M, Han F, Shi Y (2011) Expression of locus coeruleus mineralocorticoid receptor and glucocorticoid receptor in rats under single-prolonged stress. Neurol Sci 32(4):625–631

    Article  PubMed  Google Scholar 

  • Li Y, Han F, Shi Y (2013) Increased neuronal apoptosis in medial prefrontal cortex is accompanied with changes of Bcl-2 and Bax in a rat model of post-traumatic stress disorder. J Mol Neurosci 51(1):127–137

    Article  CAS  PubMed  Google Scholar 

  • Liberzon I, Martis B (2006) Neuroimaging studies of emotional responses in PTSD. Ann N Y Acad Sci 1071:87–109

    Article  PubMed  Google Scholar 

  • Liberzon I, LóPez JF, Flagel SB et al (1999) Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder. J Neuroendocrinol 11(1):11–17

    Article  CAS  PubMed  Google Scholar 

  • Lim G, Wang S, Zeng Q et al (2005) Expression of spinal NMDA receptor and PKC gamma after chronic morphine is regulated by spinal glucocorticoid receptor. J Neurosci 25(48):11145–11154

    Article  CAS  PubMed  Google Scholar 

  • Maddali KK, Korzick DH, Turk JR et al (2005) Isoform-specific modulation of coronary artery PKC by glucocorticoids. Vasc Pharmacol 42(4):153–162

    Article  CAS  Google Scholar 

  • Milad MR, Rauch SL, Pitman RK et al (2006) Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol 73(1):61–71

    Article  PubMed  Google Scholar 

  • Nemeroff CB, Bremner JD, Foa EB et al (2006) Posttraumatic stress disorder: a state-of-the-science review. J Psychiatr Res 40:1–21

    Article  PubMed  Google Scholar 

  • Oitzl MS, Fluttert M, Sutanto W et al (1998) Continuous blockade of brain glucocorticoid receptors facilitates spatial learning and memory in rats. Eur J Neurosci 10(12):3759–3766

    Article  CAS  PubMed  Google Scholar 

  • Peters LR, Raghavan M (2011) ER calcium depletion impacts chaperone secretion, innate immunity and phagocytic uptake of cells. J Immunol 187(2):919–931

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • PhelPs EA, Delgado MR, Nearing KI et al (2004) Extinction learning in humans: role of the amygdala and vmPFC. Neuron 43(6):897–905

    Article  CAS  PubMed  Google Scholar 

  • Qiu Y, Michalak M (2009) Transcriptional control of the calreticulin gene in health and disease. Int J Biochem Cell Biol 41(3):531–538

    Article  CAS  PubMed  Google Scholar 

  • Qiu J, Lou LG, Huang XY et al (1998) Nongenomic mechanisms of glucocorticoid inhibition of nicotine-induced calcium influx in PC12 cells: involvement of protein kinase C. Endocrinology 139(12):5103–5108

    CAS  PubMed  Google Scholar 

  • Qiu J, Wang CG, Huang XY et al (2003) Nongenomic mechanism of glucocorticoid inhibition of bradykinin-induced calcium influx in PC12 cells: possible involvement of protein kinase C. Life Sci 72(22):2533–2542

    Article  CAS  PubMed  Google Scholar 

  • Quirk GJ, Beer JS (2006) Prefrontal involvement in the regulation of emotion: convergence of rat and human studies. Curr Opin Neurobiol 16(6):723–727

    Article  CAS  PubMed  Google Scholar 

  • Roozendaal B, Williams CL, McGaugh JL (1999) Glucocorticoid receptor activation in the rat nucleus of the solitary tract facilitates memory consolidation: involvement of the basolateral amygdala. Eur J Neurosci 11(4):1317–1323

    Article  CAS  PubMed  Google Scholar 

  • Roozendaal B, McReynolds JR, Van der Zee EA et al (2009) Glucocorticoid effects on memory consolidation depend on functional interactions between the medial prefrontal cortex and basolateral amygdala. J Neurosci 29:14299–14308

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sailer U, Robinson S, Fischmeister FP et al (2008) Altered reward processing in the nucleus accumbens and nesial prefrontal cortex of patients with posttraumatic stress disorder. Neuropsychologia 46(11):2836–2844

    Article  PubMed  Google Scholar 

  • Takahashi T, Morinobu S, Iwamoto Y et al (2006) Effect of paroxetine on enhanced contextual fear induced by single prolonged stress in rats. Psycho Pharmacol (Beri) 189(2):165–173

    Article  CAS  Google Scholar 

  • Tipps ME, Raybuck JD, Lattal KM (2014) Substance abuse, memory, and post-traumatic stress disorder. Neurobiol Learn Mem 112c:87–100

    Article  Google Scholar 

  • Treves S, Zorzato F, Pozzan T (1992) Identification of calreticulin isoforms in the central nervous system. Biochem J 287(Pt 2):579–581

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ureshino RP, Rocha KK, Lopes GS et al (2014) Calcium signaling alterations, oxidative stress, and autophagy in aging. Antioxid Redox Signal 21(1):123–137

    Article  CAS  PubMed  Google Scholar 

  • Vassilakos A, Michalak M, Lehrman MA et al (1998) Oligosaccharide binding characteristics of the molecular chaperones calnexin and calreticulin. Biochemistry 37(10):3480–3490

    Article  CAS  PubMed  Google Scholar 

  • Vermetten E (2009) Stress, trauma, and post-traumatic stress disorder. Tijdschr Psychiatr 51(8):595–602

    CAS  PubMed  Google Scholar 

  • Wang HT, Han F, Gao JL, Shi YX (2010) Increased phosphorylation of extracellular signal–regulated kinase in the medial prefrontal cortex of the single-prolonged stress rats. Cell Mol Neurobiol 30:437–444

    Article  PubMed  Google Scholar 

  • Waser M, Mesaeli N, Spencer C et al (1997) Regulation of calreticulin gene expression by calcium. J Cell Biol 138(3):547–557

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wehmeyer L, Du Toit A, Lang DM et al (2014) Lipid raft- and protein kinase C-mediated synergism between glucocorticoid- and gonadotropin-releasing hormone signaling results in decreased cell proliferation. J Biol Chem 289(14):10235–10251

    Article  CAS  PubMed  Google Scholar 

  • Wen Y, Li B, Han F et al (2012) Dysfunction of calcium/calmodulin/CaM kinase IIα cascades in the medial prefrontal cortex in post-traumatic stress disorder. Mol Med Rep 6:1140–1144

    CAS  PubMed  Google Scholar 

  • Yamamoto S, Morinobu S, Takei S et al (2009) Single prolonged stress: toward an animal model of posttraumatic stress disorder. Depress Anxiety 26(12):1110–1117

    Article  PubMed  Google Scholar 

  • Zelikowsky M, Hersman S, Chawla MK et al (2014) Neuronal ensembles in amygdala, hippocampus, and prefrontal cortex track differential components of contextual fear. J Neurosci 34(25):8462–8466

    Article  PubMed Central  PubMed  Google Scholar 

  • Zhao D, Han F, Shi Y (2014) Effect of glucose-regulated protein 94 and endoplasmic reticulum modulator CasPase-12 in medial prefrontal cortex in a rat model of posttraumatic stress disorder. J Mol Neurosci 54(2):147–155

    Article  CAS  PubMed  Google Scholar 

  • Zhe D, Fang H, Yuxiu S (2008) Expressions of Hippocampal mineralocorticoid receptor(MR)and glucocorticoid receptor (GR) in the single-prolonged stress-rats. Acta Histochem Cytochem 41(4):89–95

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant from the National Natural Science Foundation of China (No.31200772), Research Fund from the Doctoral programme of higher education of China (No.20132104110021) and Liaoning Provincial Natural Science Foundation of China (NO.2014021053). What’s more, we feel grateful for the technical support from the China Medical University Experiment Center. Our thanks go to Professor Shi Yuxiu and Professor Han Fang for the guidance and discussion.

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  1. PTSD Lab, Department of Histology and Embryology, Institute of Pathology and Pathophysiology, Basic Medical Sciences College, China Medical University, Shenyang, China

    Lili Wen, Fan Han & Yuxiu Shi

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  1. Lili Wen
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  2. Fan Han
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  3. Yuxiu Shi
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Correspondence to Yuxiu Shi.

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Wen, L., Han, F. & Shi, Y. Changes in the Glucocorticoid Receptor and Ca2+/Calreticulin-Dependent Signalling Pathway in the Medial Prefrontal Cortex of Rats with Post-traumatic Stress Disorder. J Mol Neurosci 56, 24–34 (2015). https://doi.org/10.1007/s12031-014-0464-7

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  • DOI: https://doi.org/10.1007/s12031-014-0464-7

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