Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression

Abstract

Post-traumatic stress disorder (PTSD) can develop following severe trauma, but the extent to which genetic and environmental risk factors contribute to individual clinical outcomes is unknown. Here, we compared transcriptional responses to hydrocortisone exposure in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and peripheral blood mononuclear cells (PBMCs) from combat veterans with PTSD (n = 19 hiPSC and n = 20 PBMC donors) and controls (n = 20 hiPSC and n = 20 PBMC donors). In neurons only, we observed diagnosis-specific glucocorticoid-induced changes in gene expression corresponding with PTSD-specific transcriptomic patterns found in human postmortem brains. We observed glucocorticoid hypersensitivity in PTSD neurons, and identified genes that contribute to this PTSD-dependent glucocorticoid response. We find evidence of a coregulated network of transcription factors that mediates glucocorticoid hyper-responsivity in PTSD. These findings suggest that induced neurons represent a platform for examining the molecular mechanisms underlying PTSD, identifying biomarkers of stress response, and conducting drug screening to identify new therapeutics.

In vitro modeling of the neurobiological effects of glucocorticoids: A review

“…Interestingly, no significant effect of the risk versus resilient rs1360780 allele were observed ( Nold et al, 2021 ). Despite both studies not illustrating any effect of the genotype on expression, this is not representative of the field as a whole, with gene-environment interaction being demonstrated in human studies ( Klengel et al, 2013 ; Czamara et al, 2019 ), and iPSC-derived models ( Seah et al, 2022 ; Dobrindt et al, 2020 ). Additionally, these studies highlight the importance of cell type differential responsiveness to GCs and GR-sensitivity, but also the importance of in vitro studies in unraveling the genetic risk underlying SRDs.…”

“…3 for comparison between models). Differences in culture and differentiation protocols among in vitro models, and specifically in reprogramming and differentiation protocols within PSCs (transdifferentiation versus indirect conversion) ( Hoffmann et al, 2019 ) are also major sources of variation (some more than others) that could influence the GC-induced phenotype (as seen in ( Seah et al, 2022 )). Nevertheless as showcased in Fig.…”

“…Genetic variants, including single nucleotide polymorphisms (SNPs), are strongly associated with several psychiatric disorders ( Committee, 2009 ), and alter the response of a single individual to particular substances such as drugs, and other environmental stimuli ( Matsa et al, 2016 ). The use of in vitro models, and in particular iPSCs, for the investigation of genetic vulnerability of psychiatric disorders has gained increased attention ( Seah et al, 2022 ; Hoffmann et al, 2020 ), and can be used for understanding how genetic variants create differential cellular responses to, for instance, a GC challenge in vitro ( Hu et al, 2021 ).…”

“…Looking at the influence of environmental factors in the presence of underlying genetic vulnerability, Seah et al generated iPSC-derived mixed forebrain neurons and NGN2-induced neurons from combat-exposed veterans with and without PTSD ( Seah et al, 2022 ). Following exposure to different concentrations of DEX, differentially expressed genes were observed for each of the different concentrations in NGN2 neurons and, to a lesser extent, in mixed forebrain neurons.…”

“…These results further highlight the role of astrocytes in the stress response and FKBP5- associated functions. ( Seah et al, 2022 ) Human iPSC-derived mixed forebrain neurons and induced-NGN2 neurons dexamethasone and hydrocortisone 100, 1000, and 2500 nM 6 and 24 h GC exposure produces cell-type specific stress responses and concentration-dependent differential genetic expression that could be used as a diagnostic tool for PTSD risk. ( Hay et al, 2014 ) Primary neonate neurons dexamethasone 50 μM 16 h SNPGR, is a DEX response element of the TAC1 (gene encoding substance-P) promoter region which leads to an increased promoter activity if carrying the T-allele.…”