title: Single-prolonged stress induces endoplasmic reticulum-dependent apoptosis in the hippocampus in a rat model of post-traumatic stress disorder.
abstract: BACKGROUND
  Our previous research indicated that apoptosis induced atrophy in the hippocampus 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) induces apoptosis in the hippocampus of PTSD rats by examining the expression levels of three important indicators in the ER-related apoptotic pathway: Glucose-regulated protein (GRP) 78, caspase-12 and Ca(2+)/CaM/CaMkinaseIIα (CaMkIIα).
  
  
  METHODS
  Wistar rats were sacrificed at 1, 4 and 7 days after SPS. SPS is a reliable animal model of PTSD. The apoptotic cells in the hippocampus were assessed by TUNEL method and transmission electron microscopy (TEM). Free intracellular Ca(2+) concentration was measured. GRP78 expression was examined by immunohistochemistry, western blotting and RT-PCR. mRNA of caspase-12 and CaM/CaMkIIα were determined by RT-PCR.
  
  
  RESULTS
  Our results showed that apoptotic cells were increased in the SPS rats. TEM analysis revealed characteristic morphological changes of apoptosis in these cells. We observed that GRP78 was significantly up-regulated during early PTSD, and then recovered at 7 days after SPS. By RT-PCR, we observed that the change in caspase-12 expression level was similar to that in GRP78. Moreover, the free intracellular Ca(2+) concentration was significantly higher at 1 day after SPS and decreased in 7 days. CaM expression increased significantly, while CaMKIIα expression decreased significantly in the hippocampus at 1 day after SPS.
  
  
  CONCLUSIONS
  SPS induced change in the expression levels of GRP78, caspase-12 and Ca(2+)/CaM/CaMkIIα in the hippocampus of PTSD rats indicated that the endoplasmic reticulum pathway may be involved in PTSD-induced apoptosis.
authors.affiliation: PTSD Laboratory, Department of Histology and Embryology, Institute of Pathology and Pathophysiology, China Medical University, Shenyang, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Han
authors.forename: Shengnan
authors.initials: S
authors.lastname: Yan
authors.forename: YuXiu
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002147:Calmodulin; D053454:Caspase 12; D006360:Heat-Shock Proteins; D012333:RNA, Messenger; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP
references.citation: Neuroscience. 2003;118(2):491-9
references.pmid: 12699784
references.citation: Annu Rev Biochem. 2000;69:217-45
references.pmid: 10966458
references.citation: Nature. 1998 Dec 10;396(6711):584-7
references.pmid: 9859994
references.citation: Can J Psychiatry. 2002 Sep;47(7):666-70
references.pmid: 12355679
references.citation: Psychol Med. 2005 Oct;35(10):1421-31
references.pmid: 16164766
references.citation: Differentiation. 2006 Jun;74(5):195-211
references.pmid: 16759286
references.citation: Environ Health Perspect. 2006 Jun;114(6):859-64
references.pmid: 16759985
references.citation: Cancer Biol Ther. 2007 May;6(5):732-42
references.pmid: 17387273
references.citation: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references.pmid: 17565364
references.citation: Genes Dev. 1998 Jun 15;12(12):1812-24
references.pmid: 9637683
references.citation: FASEB J. 1997 Sep;11(11):843-9
references.pmid: 9285482
references.citation: Science. 1999 Apr 9;284(5412):339-43
references.pmid: 10195903
references.citation: Arch Gen Psychiatry. 2005 Mar;62(3):273-81
references.pmid: 15753240
references.citation: J Biol Chem. 1990 May 5;265(13):7248-56
references.pmid: 2332429
references.citation: Brain Res. 1989 Oct 16;499(2):383-7
references.pmid: 2572303
references.citation: Cold Spring Harb Perspect Biol. 2011 Sep 01;3(9):a004424
references.pmid: 21813400
references.citation: Cogn Behav Neurol. 2003 Dec;16(4):219-24
references.pmid: 14665821
references.citation: Acta Psychiatr Scand. 2006 Apr;113(4):360-3; discussion 363-4
references.pmid: 16638081
references.citation: Mt Sinai J Med. 2004 Oct;71(5):289-97
references.pmid: 15543429
references.citation: Biochem Biophys Res Commun. 2007 Mar 2;354(1):278-83
references.pmid: 17217916
references.citation: J Clin Invest. 2002 Nov;110(10):1389-98
references.pmid: 12438434
references.citation: Ann N Y Acad Sci. 1997 Jun 21;821:1-9
references.pmid: 9238189
references.citation: Trends Biochem Sci. 2001 Aug;26(8):504-10
references.pmid: 11504627
references.citation: EMBO J. 1998 Oct 1;17(19):5708-17
references.pmid: 9755171
references.citation: J Neurophysiol. 1998 May;79(5):2288-302
references.pmid: 9582205
references.citation: Mol Cell Biol. 2003 Jul;23(13):4532-41
references.pmid: 12808095
references.citation: Int J Cell Biol. 2012;2012:493934
references.pmid: 22577383
references.citation: Biol Psychiatry. 2004 Dec 1;56(11):832-6
references.pmid: 15576059
references.citation: J Psychiatr Res. 2010 Jan;44(1):48-55
references.pmid: 19586638
references.citation: J Cell Biol. 2003 Jul 7;162(1):59-69
references.pmid: 12847083
references.citation: Nat Cell Biol. 2000 Jun;2(6):326-32
references.pmid: 10854322
references.citation: Neuroscientist. 2009 Oct;15(5):540-8
references.pmid: 19359671
references.citation: Exp Neurol. 1999 Feb;155(2):302-14
references.pmid: 10072306
references.citation: J Neurosci Res. 1998 Feb 1;51(3):293-308
references.pmid: 9486765
references.citation: Neurosci Lett. 2004 Feb 19;356(3):163-6
references.pmid: 15036620
references.citation: Ann N Y Acad Sci. 2006 Jul;1071:87-109
references.pmid: 16891565
references.citation: Expert Rev Neurother. 2011 Feb;11(2):275-85
references.pmid: 21306214
references.citation: Trends Neurosci. 2003 Aug;26(8):407-10
references.pmid: 12900170
references.citation: Genet Mol Res. 2010 Jan 26;9(1):151-61
references.pmid: 20198571
references.citation: Science. 2009 Jul 24;325(5939):477-81
references.pmid: 19556461
references.citation: Nature. 2000 Jan 6;403(6765):98-103
references.pmid: 10638761
references.citation: J Chem Neuroanat. 2010 Nov;40(3):248-55
references.pmid: 20624456
references.citation: Cell Death Differ. 2006 Mar;13(3):374-84
references.pmid: 16397578
references.citation: Nat Rev Mol Cell Biol. 2003 Jul;4(7):552-65
references.pmid: 12838338
references.citation: Nat Cell Biol. 2001 Nov;3(11):E255-63
references.pmid: 11715037
references.citation: Cancer Res. 2003 Nov 1;63(21):7284-90
references.pmid: 14612525
references.citation: J Clin Invest. 2001 May;107(10):1263-73
references.pmid: 11375416