Identification of a miRNAs signature associated with exposure to stress early in life and enhanced vulnerability for schizophrenia: New insights for the key role of miR-125b-1-3p in neurodevelopmental processes

Abstract

Epidemiological and clinical studies have provided evidence for a role of both genetic and environmental factors, such as stressful experiences early in life, in the pathogenesis of Schizophrenia (SZ) and microRNAs (miRNAs) have been suggested to play a key role in the interplay between the environment and our genome. In this study, we conducted a miRNOme analysis in different samples (blood of adult subjects exposed to childhood trauma, brain (hippocampus) of rats exposed to prenatal stress and human hippocampal progenitor cells treated with cortisol) and we identified miR-125b-1-3p as a down-regulated miRNA in all the three datasets. Interestingly, a significant down-regulation was observed also in SZ patients exposed to childhood trauma. To investigate the biological systems targeted by miR-125b-1-3p and also involved in the effects of stress, we combined the list of biological pathways modulated by predicted and validated target genes of miR-125b-1-3p, with the biological systems significantly regulated by cortisol in the in vitro model. We found, as common pathways, the CXCR4 signaling, the G-alpha signaling, and the P2Y Purigenic Receptor Signaling Pathway, which are all involved in neurodevelopmental processes. Our data, obtained from the combining of miRNAs datasets across different tissues and species, identified miR-125b-1-3p as a key marker associated with the long-term effects of stress early in life and also with the enhanced vulnerability of developing SZ. The identification of such a miRNA biomarker could allow the early detection of vulnerable subjects for SZ and could provide the basis for the development of preventive therapeutic strategies.

MicroRNA mediators of early life stress vulnerability to depression and suicidal behavior

“…Participants with any psychiatric diagnosis were excluded. Altogether, 80 miRNAs were found to be significantly differentially expressed in the early trauma group compared with participants without trauma [77]. Specifically, miR-29b-3p, miR-29c-3p, and miR-16-5p were significantly upregulated, while miR-200b-5p and miR-125b-1-3p were significantly downregulated.…”

“…Specifically, miR-29b-3p, miR-29c-3p, and miR-16-5p were significantly upregulated, while miR-200b-5p and miR-125b-1-3p were significantly downregulated. However, when they studied hippocampal miRNA expression in prenatally stressed rodents, they found decreases only in miR-125-1-3p, which was also present in cortisol-treated hippocampal progenitor cells [77]. This shows that miR-125-1-3p is specifically responsive to ELS and the effects are lasting and consistent across species.…”

“…The human literature on ELS as it relates to miRNAs is still quite limited and mostly overlaps with various psychiatric disorders. In an effort to explore the contribution of ELS to schizophrenia onset, Cattane et al [77] collected blood samples from 32 control participants (11 with and 22 without early trauma history) and used microarray to assess miRNA expression levels in whole blood. Participants with any psychiatric diagnosis were excluded.…”

“…Still, seven miRNAs were identified by more than one study as relevant to ELS experience: miR-16, miR-18a, miR-9, miR-29, miR-200, miR-125, and miR-124. MiR-16 is upregulated in the hippocampus after both maternal separation [36] and inescapable shock [76] in rodents as well as in blood from healthy individuals with an ELS history [77]. In rodents, miR-16 has previously been implicated in serotonin transmission systems [82] as well as resilience to altered behavior after chronic adult stress [83].…”

“…MiR-137, miR-181b, and miR-219-5p have consistently been identified in patients as peripheral signatures of schizophrenia regardless of ELS history [38]. In one clinical study of patients with schizophrenia and self-reported ELS history, miR-125-1-3p was significantly downregulated compared with patients without ELS [77]. Future studies in patients should utilize selfreport measures like the Childhood Trauma Questionnaire [102] to conduct analyses both on diagnostic status and ELS history; similar methods have been applied to examine differences in brain function via fMRI [103].…”