Selective lentiviral-mediated suppression of microRNA124a in the hippocampus evokes antidepressants-like effects in rats

Several lines of evidences suggest that the brain-derived neutrophic factor (BDNF) is implicated in the pathophysiology of depression. However, the molecular mechanisms are not fully understood. In the current study we aimed to investigate how genetic modulation of BDNF in the hippocampus using microRNa124a (miR124a)-expressing lentiviral vectors (LV) might affect depression-like behavior in adult rats. For this purpose, we assessed the expression level of miR124a and its direct target BDNF in the hippocampus and the cortex after 21-days exposure to social defeat stress. Results demonstrated that miR124a was up-regulated in the hippocampus but not in the cortex. In contrast, and as expected, BDNF transcripts were down-regulated. In a different set of experiments, male Wistar rats received bilateral intra-hippocampal or intra-cortical infusions of BDNF- and miR124a-expressing lentiviral vectors and depression-like behavior was assessed after 21-days social defeat stress using the novelty suppressed feeding, the sucrose preference and the forced swim tests. The results indicated that miR124a overexpression exacerbated depression-like behavior. However, an anti-depressant like effect was observed when BDNF or miR124a-silencers (siR124a) were injected into the hippocampus. Importantly, when expressed into the cortex, LV-miR124a, LV-siR124a and LV-BDNF had no effect on depression. Our findings indicate that hippocampal miR124a and its direct target BDNF play an important role in depression-like behavior. Taken together, the current results reveal, for the first time, a potential molecular regulation of miR124a on BDNF, and the pronounced behavioral consequences of this regulation shed light on the mechanisms underlying BDNF anti-depressant potential.