The purpose of the present study was to examine the changes in the molecular chaperone calreticulin (CRT), calcium signaling pathway Ca(2+)-calmodulin (CaM)-CaM kinaseIIα (CaMKIIα), and the endoplasmic reticulum (ER) apoptotic modulator caspase-12 in hippocampal neurons of rats exposed to single-prolonged stress (SPS), a model of post-traumatic stress disorder (PTSD). Molecular markers and proteins were assessed using immunohistochemistry, western blot and reverse transcript-polymerase chain reaction in rats exposed to SPS at 1 day (1d), 4 and 7 days post-stress and time matched controls. We found that at 7 days, SPS rats had the highest CRT expression. The intracellular free Ca(2+) and the CaM expression reached peak at 1 day post-SPS whereas the CaMKIIα had the opposite trend. Caspase-12 was most active at 4 days and was found to decrease thereafter. Signs of apoptosis were identified using transmission electron microscopy in the rats exposed to SPS. The results indicate that signs of ER stress in the hippocampus of rats exposed to SPS trigger the molecular changes in the intracellular cytoplasm which in turn activate the apoptotic pathway through caspase-12. Therefore, we propose that the hippocampal apoptosis could be one of the pathological mechanisms related to the memory disorders in PTSD.