BDNF alterations as consequences of childhood trauma experiences

Indeed, exposure to childhood trauma experiences is associated with increased vulnerability for several kinds of disorders including mental illnesses (van Winkel et al., 2013). This increased vulnerability is due to the fact that childhood is a critical period for the brain development, where the brain is not completely developed yet and thus high vulnerable to adverse events. The Brain-Derived Neutrotrophic factor (BDNF) is a major neuronal growth factor in the brain, regulating neurogenesis, neuronal maturation and survival, and synaptic plasticity (Tsankova et al., 2007). It has been proposed that BDNF could be the link between early life stress and the vulnerability to psychiatric disorders (Schroeder et al., 2010). The focus of this work was to investigate BDNF levels in the peripheral blood of control subjects characterized for exposures to stressful experiences during childhood. By using Real Time PCR we measured total BDNF mRNA levels and the results indicated a strong reduction of total BDNF mRNA levels in individuals exposed to stress early in life versus not exposed individuals (-32%, p<0.01 vs not exposed subjects). Then, we assessed the contribution of the different BDNF transcripts on BDNF total modulation, and we found that transcripts IV and IX were significantly reduced (-71%, p<0.05; -35%, p<0.05, respectively). In order to investigate the molecular mechanisms underlying these long lasting changes in BDNF expression, we evaluated the role of DNA methylation and miRNAs as possible epigenetic mechanisms. We assessed the DNA methylation levels of specific CpGs in both the transcripts IV and IX, however, no significant changes in association to stress exposures were observed. Then, we focused on miRNAs targeting BDNF and we identified, by using biostatistical tools, the main predicted and validated miRNAs targeting BDNF 5’ UTR region, CDS region and 3’ UTR region (total number of miRNAs = 805). Due to the high number of miRNAs targeting BDNF that we identified, we used a whole genome approach and we run a miRNome analysis. We found that 26 of the 805 miRNAs targeting BDNF are significantly up regulated in response to stress early in life; 18 targeting the 5’ UTR region, 4 targeting the CDS region and 4 targeting the 3’ UTR region (Fold Change>1.1; p<0,05 for all the 26 miRNAs). Bioinformatic analysis, using the DIANA miRPath program (v.2.0) identified the signal transduction, the neurotrophin signalling and the long-term potentiation pathways as the most significant pathways modulated by the significant miRNAs. In conclusion we found that total BDNF mRNA levels are reduced in the peripheral blood of subjects exposed to stressful experiences during childhood and that miRNAs could be in part responsible for these long lasting changes in BDNF expression. In the future, a better characterization of miRNAs modulation may identify novel targets for preventative therapies in subjects with a history of childhood trauma, which are at higher risk to develop psychiatric disorders in the adulthood.