Molecular mechanisms of D-cycloserine in facilitating fear extinction: Insights from RNAseq

Posttraumatic stress disorder (PTSD) is a severe, chronic and debilitating psychiatric disorder that can present after a life-threatening traumatic event. D-cycloserine (DCS) has been found to augment cognitive behavioural therapy by facilitating fear extinction; however, the precise molecular mechanisms are unclear. This study investigated the molecular mechanisms of intrahippocampally administered DCS in facilitating fear extinction in a rat model of PTSD. Rats were grouped into four experimental groups based on fear conditioning and intrahippocampal administration of either DCS or saline. The light/dark [L/D] avoidance test was used to differentiate maladapted (animals that displayed anxiety-like behaviour) from well-adapted (animals that did not display any anxiety-like behaviour) subgroups. Gene expression data from the left dorsal hippocampus was compared between the fear-conditioned + saline maladapted (FSM) and fear-conditioned + DCS well-adapted (FDW) groups. RNA sequencing and bioinformatics analyses identified 424 significantly downregulated and 27 significantly upregulated genes in the FDW group compared to the FSM group; 121 of the downregulated genes and nine of the upregulated genes were predicted to be biologically relevant to PTSD. Intrahippocampal DCS administration in combination with behavioural fear extinction resulted in the downregulation of genes that transcribe components within the immune, proinflammatory and oxidative stress systems. These molecules mediate neuroinflammation and cause neuronal damage. DCS also regulated genes involved in learning and memory processes, genes associated with PTSD and disorders that commonly co-occur with PTSD, such as cardiovascular diseases, digestive system diseases and nervous system diseases. These results could point to novel biological targets for the pharmacological management of PTSD