The Epigenetic Changes in a Rat Model of Post-traumatic Stress Disorder Controlled by Valproic Acid

Abstract Valproic acid (VPA) is a potent non-selective histone deacetylase (HDAC) inhibitor. HDAC inhibitors and histone proteins have been studied extensively in the literature. They have been proven effective in the learning and memory processes in psychiatric conditions, including post-traumatic stress disorder (PTSD). However, the exact mechanisms and significance of different epigenetic modulations are far less clarified. Traumatic stress results in different rates of PTSD development in clinical studies, mainly attributed to different trauma types experienced by the individuals. The treatment responses to trauma to pharmacological agents may change drastically according to gender differences. As the hippocampus has a crucial role in the memory and fear circuitry, with this study, we aimed to observe the role of HDAC inhibitor VPA on hippocampal epigenetic changes and early immediate gene activation marked by c-Fos protein in a PTSD rat model where behavioral parameters of both sexes were also considered. Our study demonstrated that freezing time and anxiety indexes were affected differently by traumatic stress in males and females; however, stress had more prominent outcomes in the female gender in both parameters. H3 acetylation was observed to be higher in saline-treated female rats than the male rats, and H4 acetylation increased in the VPA-administered stressed male rats, suggesting a possible explanation for better outcomes compared to saline-treated rats after the predator stress is applied to both groups. These results suggest that VPA positively effects learning and memory in the PTSD model, and this may be attributed to various mechanisms along with epigenetic changes.