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.

Oriana Maria Maurel,Cristina Barbagallo,Gian Marco Leggio,Salvatore Salomone,Michele Purrello,Marco Ragusa,Filippo Drago,Sebastiano Alfio Torrisi

doi:10.3390/ijms22105157

Oriana Maria Maurel, Cristina Barbagallo + Show 6 more

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https://doi.org/10.3390/ijms22105157

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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.

Highlights

brain derived neurotropic factor (BDNF) and FKBP5 were used as targets to computationally identify predicted and validated miRNAs, both in human and mouse
We found 239 miRNAs targeting BDNF and/or FKBP5 both in human or mouse
Since the analyzed miRNAs frequently showed similar variation trends in the same brain area in stressed mice, we investigated whether their expressions were statistically correlated with each other in HIP, HT, and, medial prefrontal cortex (mPFC) (Table 3)

Summary

Introduction

System, the hypothalamic–pituitary–adrenal (HPA) axis, and the immune system. These biological changes can modify the neuronal connectivity, signaling, and remodeling and are associated with the exacerbation or development of neuropsychiatric diseases, such as depression and post-traumatic stress disorder (PTSD) [1,2,3]. Cellular and molecular studies in PTSD and stress-related disorders showed the involvement of a distinct sets of HPA-axis-related genes [4,5,6]. In this context, the roles of FKBP5 (FK506 binding protein 5)

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