Molecular and cellular studies of PTSD: Postmortem transcriptome analysis and novel therapeutic targets

Abstract

The neurobiology of fear memory and extinction has been the subject of extensive research efforts that have increased our understanding of the brain regions, circuitry, and the cellular and molecular determinants of fear memory processes. However, the inability to access and directly study the brains of PTSD patients has made it difficult to translate the rodent fear memory studies to understand the neurobiological underpinnings of PTSD. The formation of a PTSD brain repository has recently been undertaken to address this issue. This will allow for high throughput gene expression and proteome analysis that can be coupled with epigenetic and genomic approaches to characterize the molecular alterations underlying PTSD. Preliminary studies using next generation RNA sequencing have identified PTSD specific gene expression alterations in the prefrontal cortex (PFC). The approaches used for transcriptome analysis and early findings regarding two glucocorticoid regulated genes of interest, FKBP5 and SGK1 are discussed, and the consequences of altered SGK1 are presented. Altered SGK1 could contribute to synaptic alterations in PFC subregions that could contribute to loss of inhibitory control and extinction of fear memories. Based on these findings, we discuss new studies demonstrating that ketamine can increase synapse number in the PFC and enhance the extinction of fear memory in rodent models and improve symptoms in PTSD patients. Continued molecular and cellular characterization of postmortem brain tissue of PTSD subjects will further define the neurobiology of PTSD and identify novel targets for safe and more efficacious treatments.

Keywords: RNA sequencing; glucocorticoid; ketamine; prefrontal cortex.