Dysregulation of miR-15a-5p, miR-497a-5p and miR-511-5p Is Associated with Modulation of BDNF and FKBP5 in Brain Areas of PTSD-Related Susceptible and Resilient Mice

Abstract

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder occurring in susceptible individuals following a traumatic event. Understanding the mechanisms subserving trauma susceptibility/resilience is essential to develop new effective treatments. Increasing evidence suggests that non-coding RNAs, such as microRNAs (miRNAs), may play a prominent role in mediating trauma susceptibility/resilience. In this study, we evaluated the transcriptional expression of two key PTSD-related genes (FKBP5 and BDNF) and the relative targeting miRNAs (miR-15a-5p, miR-497a-5p, miR-511-5p, let-7d-5p) in brain areas of PTSD-related susceptible and resilient mice identified through our recently developed mouse model of PTSD (arousal-based individual screening (AIS) model). We observed lower transcript levels of miR-15a-5p, miR-497a-5p, and miR-511a-5p in the hippocampus and hypothalamus of susceptible mice compared to resilient mice, suggesting that the expression of these miRNAs could discriminate the two different phenotypes of stress-exposed mice. These miRNA variations could contribute, individually or synergically, to the inversely correlated transcript levels of FKBP5 and BDNF. Conversely, in the medial prefrontal cortex, downregulation of miR-15a-5p, miR-511-5p, and let-7d-5p was observed both in susceptible and resilient mice, and not accompanied by changes in their mRNA targets. Furthermore, miRNA expression in the different brain areas correlated to stress-induced behavioral scores (arousal score, avoidance-like score, social memory score and PTSD-like score), suggesting a linear connection between miRNA-based epigenetic modulation and stress-induced phenotypes. Pathway analysis of a miRNA network showed a statistically significant enrichment of molecular processes related to PTSD and stress. In conclusion, our results indicate that PTSD susceptibility/resilience might be shaped by brain-area-dependent modulation of miRNAs targeting FKBP5, BDNF, and other stress-related genes.

MicroRNA Let-7e in the Mouse Prefrontal Cortex Differentiates Restraint-Stress-Resilient Genotypes from Susceptible Genotype

“…The expression of Bdnf was increased following RS in the PFC of WT mice but did not change in the PFC of NET-KO and SWR/J mice (Supplement S4). This is in line with the studies by Maurel and coworkers, who discovered an increase in the expression of mRNA encoding Bdnf in the PFC of stress-susceptible mice and no change in stress-resilient mice [19].…”

“…The decrease in miR let-7b expression was described in the blood of students under exam-induced stress conditions [17], similarly to patients diagnosed with major depression, where the expression of miR let-7c was also decreased in the blood of these patients [18]. Recently, Maurel et al [19] showed a decrease in mmu-let-7d-5p expression in the PFC of mice that were subjected to RS (24 h), however with no correlation with the level of its mRNA targets.…”

The miRNome of Depression

“…In animal studies, reduced miR-511 expression was observed in the prefrontal cortex in rats, following chronic unpredictable stress or dexamethasone administration [ 82 ]. In a mouse model of post-traumatic stress disorder (PTSD), lower miR-511 transcript levels were observed in the hippocampus and hypothalamus of stress-susceptible animals, while in the medial prefrontal cortex both stress-susceptible and resilient animals had lower levels of miR-511 [ 83 ]. Another interesting study was performed by Issler et al [ 84 ].…”

BDNF Therapeutic Mechanisms in Neuropsychiatric Disorders

“…This also applies for the complex BDNF-serotonin interactions in the understanding and treatment of various psychopathologies [ 213 ], especially in mood disorders such as anxiety and depression [ 214 ]. Interestingly, stress-induced BDNF dysregulation is brain region-specific, as observed in post-traumatic stress disorder (PTSD) in which BDNF mRNA is differentially downregulated in certain brain regions while being upregulated in others [ 215 , 216 ]. This further supports the BDNF stress-sensitivity hypothesis that BDNF dysregulation, as with the Val66Met polymorphism, predicts vulnerability to stress [ 217 ].…”