Analysis of miRNome expression profile in hippocampus of rats treated with antidepressants

Abstract

MicroRNAs (miRNAs) are small, non-coding RNAs with a key role in regulating gene expression at post-transcriptional level. Recent investigations suggested that dysregulation in miRNA expression may be critical for mental disorders pathophysiology, including mood disorders, and in psychotropic drugs action, such as mood stabilizers and antidepressants (ADs). Aim of the studies presented was to analyze whether modulation of hippocampal miRNome could be part of the mode of action of different ADs, fluoxetine, desipramine and agomelatine. Moreover, in order to assess the time course of ADs effects, treatments were performed for various time lengths (3,7 or 21 days). Rat hippocampal miRNome expression was investigated by means of TaqMan Rodent MicroRNA Arrays. We found that all ADs induced a significant modulation of hippocampal miRNome, although with different time-dependent effects. Indeed, all ADs significant modulated miRNA expression already after 3 days of treatment with the most pronounced effect by agomelatine (37 miRNAs, mainly down-regulated); whereas both fluoxetine and desipramine modified the expression of 8 different miRNAs. After 7 days, the greater number of miRNAs was modulated by fluoxetine (35 miRNAs, mainly up-regulated), while desipramine and agomelatine modulated the expression of 13 and 22 miRNAs, respectively. Finally, 21 days of agomelatine treatment modulated the expression of 6 miRNAs. Interestingly, some of the miRNAs were found to be similarly affected by at least two of the different ADs. A bio-informatic analysis allowed the identification of putative miRNA targets and signalling pathways modulated by the identified miRNAs. The predicted target genes of miRNAs are involved in several pathways related to neuronal functions and ADs mechanism of action; moreover, many of the putative target genes, in particular those of miRs modulated by agomelatine, are enriched in pathways related to DNA/RNA regulation and epigenetic mechanisms. A number of putative miRNA target genes have been selected for validation studies by means of mRNA/protein expression analyses. The results of these work, showing that AD treatments induce early and time-dependent modifications in the expression of hippocampal miRNAs, could be of help to better clarify the ADs mechanism of action and to identify new putative targets for the development of novel drugs with greater efficacy and a more rapid onset of action.