Modeling gene x environment interactions in PTSD using glucocorticoid-induced transcriptomics in human neurons

Abstract

Post-traumatic stress disorder (PTSD) results from severe trauma exposure, but the extent to which genetic and epigenetic risk factors impact individual clinical outcomes is unknown. We assessed the impact of genomic differences following glucocorticoid administration by examining the transcriptional profile of human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and live cultured peripheral blood mononuclear cells from combat veterans with PTSD (n=5) and without PTSD (n=5). This parallel examination in baseline and glucocorticoid-treated conditions resolves cell-type specific and diagnosis-dependent elements of stress response, and permits discrimination of gene expression signals associated with PTSD risk from those induced by stress. Computational analyses revealed neuron-specific glucocorticoid-response expression patterns that were enriched for transcriptomic patterns observed in clinical PTSD samples. PTSD-specific signatures, albeit underpowered, accurately stratify veterans with PTSD relative to combat-exposed controls. Overall, in vitro PTSD and glucocorticoid response signatures in blood and brain cells represent exciting new platforms with which to test the genetic and epigenetic mechanisms underlying PTSD, identify biomarkers of PTSD risk and onset, and conduct drug-screening to identify novel therapeutics to prevent or ameliorate clinical phenotypes.

Stress-in-a-dish

“…While this is possibly due to small sample size, another reason could be attributed to the reversing effects of chronic CORT on DNMT expression, which has been shown to decrease following stress and GC exposure [29,30]. Moreover, changes in DNMT levels have been associated with effects of chronic stress and neurodevelopmental disorders, including schizophrenia [31], and PTSD [32].…”

“…While MR dysregulation has also been reported in SRMDs [28], the detrimental effects of GCs are predominantly ascribed to GR-mediated signaling, and hence most in vitro GC studies focus on the downstream effects of GR activation. This has improved our knowledge on the effects of GCs on several neuronal processes including neurogenesis, neuronal morphology, synaptogenesis, and synaptic plasticity, among others [29], and have helped us better understand the involvement of GCs in SRMDs [30][31][32].…”

“…Non-genomic effects are rapid and include changes in intracellular signaling pathways, and the modulation of the activity of enzymes and transporters [31]. GR and MR control a number of neuronal processes including proliferation, neuronal differentiation, and excitability, eventually impacting mood, cognition and behavior functions, all crucial in the regulation of acute or chronic stress [32]. Additionally, the GR plays a big role in negative feedback regulation of CORT release [33].…”

“…A key player in the regulation of GR expression is FKBP prolyl isomerase 5 (FKBP5), acting as a co-chaperone to the GR influencing its sensitivity to GCs [30]. Increasing evidence points towards dysregulation of the neuroendocrine system in subsets of patients with PTSD [31] and MDD [32], predominantly within the HPA-axis [33,34], even though these are not always consistent. HPA-axis dysregulation can be measured with the dexamethasone (DEX) suppression tests (DST).…”

“…Recent developments in the field of CPART make the use of in vitro stress models even more relevant [3], since it allows to investigate GC-induced cellular responses in the context of the genetic background of individuals expressing differential susceptibility to develop SRMDs. Indeed, the identification of unique gene expression signatures and related pathways implicated in stress vulnerability, have been identified in neurons and glia from iPSCs derived from SRMD patients [18,[32][33][34][35]. These models can also be used to examine the effects of genetic risk variants of SRMDs, e.g., polymorphisms in NR3C1 (the gene coding for GR) [36], or differential responses to GC exposure between iPSC-derived neurons from healthy and SRMD patients [18,32].…”