TIME-DEPENDENT EFFECTS OF ANTIDEPRESSANTS ON HIPPOCAMPAL MIRNOME

MicroRNAs (miRNAs) are small non-coding RNA predicted to regulate more than half of all protein-coding genes. Promising evidence from recent preclinical and clinical studies suggests that miRNAs may be crucial for the pathophysiology of Major Depression (MD) and antidepressant (AD) response. Aims of our study were to investigate: 1) the effects of two different ADs, fluoxetine and desipramine, on rat hippocampal miRNome expression; 2) the time course of AD action on miRNA expression, with treatments of different length (3/7/14 days). We found an early and significant effect of ADs, although with a different time-dependent profile for the two drugs. After 3 days of treatment, FLX down-regulated 8 miRNAs while DMI up-regulated the expression of 9 miRNAs. A more pronounced effect was found after 7 days, with 35 miRNAs modulated by FLX and 13 by DMI. Interestingly, 8 of them were similarly upregulated by both ADs. Finally, after 14 days of treatment FLX modulated 4 miRNAs and DMI 18 miRNAs. Bioinformatic analysis, performed in order to identify putative target genes and signaling pathways of miRNAs modulated by AD treatments, showed a significant enrichment of miRNA target genes in pathways related to neuronal function, many of which were previously associated to both MD pathophysiology and AD mechanism of action. Our results, showing early and time-dependent modifications in hippocampal miRNome expression by ADs, could provide new bases for the understanding of MD and AD efficacy that will advance the identification of innovative pharmacological targets for the treatment of the disease.