Antidepressant-like effect of ginsenoside Rb1 on potentiating synaptic plasticity via the miR-134-mediated BDNF signaling pathway in a mouse model of chronic stress-induced depression

Abstract

Background: Brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) plays a critical role in the pathogenesis of depression by modulating synaptic structural remodeling and functional transmission. Previously, we have demonstrated that the ginsenoside Rb1 (Rb1) presents a novel antidepressant-like effect via BDNF-TrkB signaling in the hippocampus of chronic unpredictable mild stress (CUMS)-exposed mice. However, the underlying mechanism through which Rb1 counteracts stress-induced aberrant hippocampal synaptic plasticity via BDNF-TrkB signaling remains elusive.

Methods: We focused on hippocampal microRNAs (miRNAs) that could directly bind to BDNF and are regulated by Rb1 to explore the possible synaptic plasticity-dependent mechanism of Rb1, which affords protection against CUMS-induced depression-like effects.

Results: Herein, we observed that brain-specific miRNA-134 (miR-134) could directly bind to BDNF 3'UTR and was markedly downregulated by Rb1 in the hippocampus of CUMS-exposed mice. Furthermore, the hippocampus-targeted miR-134 overexpression substantially blocked the antidepressant-like effects of Rb1 during behavioral tests, attenuating the effects on neuronal nuclei-immunoreactive neurons, the density of dendritic spines, synaptic ultrastructure, long-term potentiation, and expression of synapse-associated proteins and BDNF-TrkB signaling proteins in the hippocampus of CUMS-exposed mice.

Conclusion: These data provide strong evidence that Rb1 rescued CUMS-induced depression-like effects by modulating hippocampal synaptic plasticity via the miR-134-mediated BDNF signaling pathway.

Keywords: AAV9, adeno-associated viral serotype 9; AKT, protein kinase B; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; ANOVA, analysis of variance; BDNF, brain-derived neurotrophic factor; BDNF–TrkB signaling; CMC-Na, carboxymethyl cellulose sodium; CREB, cAMP response element-binding protein; CUMS, chronic unpredictable mild stress; CaMKII, Ca2+/calmodulin-dependent protein kinase II; DG, dentate gyrus; Depression; ERK1/2, extracellular regulatory protein kinase; FST, forced swimming test; GAP-43, growth-associated protein 43; GSK-3β, glycogen synthase kinase-3β; Ginsenoside Rb1; GluR1, AMPAR subunit glutamate receptor 1; HFS, high-frequency stimulation; IACUC, Institutional Animal Care and Use Committee; ICR, Institute of Cancer Research; LIMK1, LIM-kinase 1; LTD, long-term depression; LTP, long-term potentiation; MAP-2, microtubule-associated protein-2; MAPK, mitogen-activated protein kinase; MDD, major depressive disorder; NMDAR, N-methyl-D-aspartic acid receptor; NR2A, NMDAR subunit 2A; NR2B, NMDAR subunit 2B; NeuN, neuronal nuclei; OFT, open field test; PI3K, phosphatidylinositol 3-kinase; PSD, postsynaptic density; PSD-95, postsynaptic density protein 95; Rb1, ginsenoside Rb1; SEM, standard error of the mean; SPT, sucrose preference test; Syn, synaptophysin; Synaptic plasticity; TST, tail suspension test; TrkB, tropomyosin-related kinase B; fEPSPs, field excitatory postsynaptic potentials; i.g., intragastrically; miR-134; miR-134, miRNA-134; miRNAs, microRNAs; qRT-PCR, quantitative real-time PCR.