- Post-traumatic stress disorder (PTSD) is unique among psychiatric disorders since there is an explicit requirement for the presence of a well-defined precipitating environmental event. This suggests the participation of adaptable molecular processes such as epigenetic modifications, including acetylation and methylation of histones and DNA methylation. In the present study we investigated whether changes in DNA methylation are associated with the effects of traumatic stressor, using a validated PTSD rat model. Screening of genomic DNA methylation patterns revealed that maladaptation to traumatic stress is associated with numerous changes in the methylation pattern of rat hippocampus. Of the differentially methylated genes revealed by this global screening, Disks Large-Associated Protein (Dlgap2) was of special interest, demonstrating an increase in a specific methylation site which was associated with a reduction in its gene expression in PTSD-like compared to non-PTSD-like rats. The association between the methylation rate and Dlgap2 expression was further substantiated by re-dividing the rats according to their methylation state. A significantly higher expression was observed in the non-methylated compared to methylated rats. In addition, taking all rats as one group revealed a significant correlation between their behavioural stress responses and Dlgap2 transcript levels. These results suggest that alterations in global methylation pattern are involved in behavioural adaptation to environmental stress and pinpoint Dlgap2 as a possible target in PTSD.