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

Abstract

Summary 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 intracortical 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. #

microRNA-124: a putative therapeutic target and biomarker for major depression

“…In contrast, another study by Bahi et al [16] reported that virus-mediated miR-124 overexpression exacerbated, whereas inhibition decreased, stress-induced depressionlike behavior in rodents [16]. The differences in these two findings are not clearly known; however, model species, genetic Figure 1.…”

“…Whereas in Higuchi study [15], AAV vectors were used with the Camk2a promoter to overexpress miR-124 specifically in excitatory neurons, Bahi et al [16] used lentiviral vector where expression was driven by cytomegalovirus promoter. This suggests that the role of miR-124 in stress/depression may be cell type specific.…”

The recent progress in animal models of depression

“…Some studies have also shown that miRNAs can induce depressive-like phenotype. Recently, Bahi et al 2014 found that hippocampal miR-124a overexpression can contribute to social stress-induced depression through suppressing BDNF expression. The study also showed that miR-124a was up-regulated in the hippocampus but not in the cortex and BDNF transcripts were down regulated.…”

The link between long noncoding RNAs and depression

“…Moreover, inhibition of BDNF-AS by administrating a sequence-specific inhibitor called an antagoNAT or knockdown of BDNF-AS by siRNA both induce up-regulation of BDNF mRNA and protein expression in vitro and in vivo, leading to increased glial-derived neurotrophic factor (GDNF) and ephrin receptor B2 (EPHB2) mRNA as well as enhanced neurite outgrowth and maturation (Modarresi et al, 2012). Additionally, in the 3ʹ untranslated region (3ʹUTR) of BDNF appears a sequence complementarity of this noncoding transcript, meanwhile there also contains regulatory miRNA-binding sites such as miR-124a (Bahi et al, 2014). Intriguingly, miR-124 is demonstrated to modulate depression and related neurobehavioral deficits, therefore BDNF-AS may partly function to inhibit miR-124 binding to BDNF (Kocerha et al, 2015), suggesting an important role of BDNF-AS in MDD (Fig.…”