Knockdown of miR-124 Reduces Depression-like Behavior by Targeting CREB1 and BDNF

Abstract

Aims: To explore the role of miR-124 in depression and its potential targets. Background: Depression is one of the most common mental illnesses, and symptoms include depression, decreased interest, and severe cases with suicidal tendencies. Objective: As a brain-specific microRNA, the mechanism of miR-124 in depression has not been clarified. The present study aimed to explore the role of miR-124 in depression and its potential targets. Methods: The depression model was first replicated by the chronic unpredictable mild stress (CUMS) method. miR-124 antagomir was injected into the hippocampus of CUMS rats. Sucrose preference test (SPT), open-field test (OFT), elevated-plus maze (EPM), and forced swimming test (FST) were used to analyze the depression-like behavior. The content of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) in hypothalamus was analyzed by ELISA. qRT-PCR and western blot assay were used to functional analysis. Results: miR-124 expression was up-regulated in the hippocampus of CUMS -induced depression model rats, while CREB1 and BDNF were down-regulated. Administration of miR-124 antagomir in hippocampus inhibited miR-124 expression in hippocampus of CUMS rats. Additionally, SPT, OFT, EPM, and FST also showed that miR-124 antagomir can reduce the depression-like behavior of CUMS rats. Furthermore, miR-124 antagomir injection increased the levels of NE, DA and 5-HT in the hypothalamus of CUMS rats. Moreover, miR-124 antagomir injection increased the expression of cyclic AMP-responsive element binding protein1 (CREB1) and brain-derived neurotrophic factor (BDNF) in hippocampus. Using a dual luciferase reporter assay, it was confirmed that miR-124 directly targets the 3'UTR of CREB1 and BDNF genes. Conclusion: Knockdown of miR-124 can improve depression-like behavior in CUMS-induced depressive rats, which may be related at least in part to the up-regulation of CREB1 and BDNF expression in the hippocampus.

The miRNome of Depression

“…Interestingly, the role of miR-124-3p in the regulation of stress-related behaviors was also observed in animal studies. For instance, chronic corticosterone administration induced an increased expression level of miR-124-3p in the prefrontal cortex of rats [ 85 ], while inhibition of miR-124-3p by its antagomir in the hippocampus was able to reverse stress-induced depressive-like behavior in mice exposed to chronic corticosterone injections [ 164 ] or rats subjected to chronic unpredictable stress [ 165 ]. However, the role of miR-124-3p in the regulation of brain function in vivo may be more complex and region specific, since induced genetic miR-124-1 haploinsufficiency also contributed to the development of behavioral deficits, such as impaired prepulse inhibition or social deficits in mice [ 166 ], while decreased expression levels of miR-124-3p in the amygdala occurred following exposure of animals to acute stress [ 167 ].…”

Hippocampal Glycerol-3-Phosphate Acyltransferases 4 and BDNF in the Progress of Obesity-Induced Depression

“…Depression model rats showed overexpression of miR-124 and down-regulation of CREB1 and BDNF in the hippocampus. While knocking down miR-124 improved depression-like behavior in depression rats, which might be related to the increased expression of CREB1 and BDNF in the hippocampus ( 64 ). Our study found out downregulation of AMPK and CREB in high-fat fed mice.…”

Non-coding RNAs in depression: Promising diagnostic and therapeutic biomarkers

“…Compared with normal rats, 26 miRNAs with differential expression in prefrontal cortex were detected in chronic corticosterone-induced depressed rats, and these miRNAs regulated genes that are critical to stress response and could result in depressive-like behaviour via a hyperactive hypothalamic-pituitary-adrenal axis [30]. However, although multiple miRNAs have been identified in brain tissues from depressive-like rodent models, so far only expression of miR-124 showed a relatively consistent increase in depressed rodents compared with normal rodents among different research groups [30][31][32][33][34][35]. In addition, to obtain more direct evidence that supports miRNAs as clinical biomarkers of depression, post-mortem brain tissues, including prefrontal cortex, anterior cingulate cortex, have been used as an important resource to investigate miRNAs changes between healthy and depressed subjects.…”