microRNA-15b contributes to depression-like behavior in mice by affecting synaptic protein levels and function in the nucleus accumbens

Abstract

Major depression is a prevalent affective disorder characterized by recurrent low mood. It presumably results from stress-induced deteriorations of molecular networks and synaptic functions in brain reward circuits of genetically-susceptible individuals through epigenetic processes. Epigenetic regulator microRNA-15b inhibits neuronal progenitor proliferation and is up-regulated in the medial prefrontal cortex of mice that demonstrate depression-like behavior, indicating the contribution of microRNA-15 to major depression. Using a mouse model of major depression induced by chronic unpredictable mild stress (CUMS), here we examined the effects of microRNA-15b on synapses and synaptic proteins in the nucleus accumbens of these mice. The application of a microRNA-15b antagomir into the nucleus accumbens significantly reduced the incidence of CUMS-induced depression and reversed the attenuations of excitatory synapse and syntaxin-binding protein 3 (STXBP3A)/vesicle-associated protein 1 (VAMP1) expression. In contrast, the injection of a microRNA-15b analog into the nucleus accumbens induced depression-like behavior as well as attenuated excitatory synapses and STXBP3A/VAMP1 expression similar to the down-regulation of these processes induced by the CUMS. We conclude that microRNA-15b-5p may play a critical role in chronic stress-induced depression by decreasing synaptic proteins, innervations, and activities in the nucleus accumbens. We propose that the treatment of anti-microRNA-15b-5p may convert stress-induced depression into resilience.

Abnormal expression profile of plasma-derived exosomal microRNAs in patients with treatment-resistant depression

“…The miR-335 participates in treating severe depression by targeting glutamate metabotropic receptor 4 (GRM4) [ 54 ]. miR-15b is upregulated in the medial prefrontal cortex of depression like mice [ 55 ]. miR-101 is decreased in the ventrolateral orbital cortex (VLOs) of chronic unpredictable mild stress (CUMS) rat brain and targets dual-specific phosphatase 1 (DUSP1) to modulate depressive-like behaviors [ 56 ].…”

Early-life stress induces genome-wide sex-dependent miRNA expression and correlation across limbic brain areas in rats

“…Using chronic unpredictable mild stress in male animals, Fang et al found small increases in miR-451-5p expression in rat serum exosomes [ 48 ]; we also found a small increase in miR-451-5p in the hippocampus in males, yet we found further increase in female MS animals. Another study using the mouse chronic unpredictable mild stress model found that increased miR-15b-5p induced depression-like behavior and reduced the numbers of neuron boutons from medial PFC [ 56 ]. In MS animals, we found increases in miR-15b-3p in the PFC, which could suggest neuronal morphology changes.…”

MicroRNA Sequencing Analysis in Obstructive Sleep Apnea and Depression: Anti-Oxidant and MAOA-Inhibiting Effects of miR-15b-5p and miR-92b-3p through Targeting PTGS1-NF-κB-SP1 Signaling

“…In line with our findings, miR-15b has been shown to inhibit angiogenesis in proliferative diabetic retinopathy via targeting VEGFA, inhibit vascular smooth muscle cells in peripheral artery disease via targeting IGF1R, counteract senescence-associated mitochondrial dysfunction in skin aging via targeting SIRT4, and suppress Th17 Differentiation in multiple sclerosis by targeting O-GlcNAc [ 42 , 43 , 44 , 45 ]. In contrast, miR-15b has been found to augment cell apoptosis in Parkinson’s disease via targeting the GSK-3β/β-catenin signaling pathway, contribute to depression-like behavior in mice by affecting synaptic protein levels and function in the nucleus accumbens, deteriorate cardiomyocyte apoptosis in myocardial infarction via targeting Bcl-2/MAPK3, and contribute to extra-cellular matrix degradation in intervertebral disc degeneration via targeting SMAD3 [ 46 , 47 , 48 , 49 ]. In accordance with our findings, miR-92b-3p can suppress angiotensin II-induced cardiomyocyte hypertrophy via targeting HAND2, protect astrocyte neurons against oxygen and glucose deprivation, promote spinal cord neurite growth and functional recovery through the PTEN/AKT pathway [ 50 , 51 , 52 ].…”