Chronic stress exerts profound negative effects on cognitive and emotional behaviours and is a major risk factor for the development of neuropsychiatric disorders. However, the molecular links between chronic stress and its deleterious effects on neuronal and synaptic function remain elusive. Here, using a combination of in vitro and in vivo approaches, we demonstrate that the upregulation of miR-186-5p triggered by chronic stress may be a key mediator of such changes, leading to synaptic dysfunction. Our results show that the expression levels of miR-186-5p are increased both in the prefrontal cortex (PFC) of mice exposed to chronic stress and in cortical neurons chronically exposed to dexamethasone. Additionally, viral overexpression of miR-186-5p in the PFC of naïve mice induces anxiety- and depressive-like behaviours. The upregulation of miR-186-5p through prolonged glucocorticoid receptor activation in vitro, or in a mouse model of chronic stress, differentially affects glutamatergic and GABAergic synaptic transmission, causing an imbalance in excitation/inhibition that leads to altered neuronal network activity. At glutamatergic synapses, we observed both a reduction in synaptic AMPARs and synaptic transmission, whereas GABAergic synaptic transmission was strengthened. These changes could be rescued in vitro by a miR-186-5p inhibitor. Overall, our results establish a novel molecular link between chronic glucocorticoid receptor activation, the upregulation of miR-186-5p and the synaptic changes induced by chronic stress, that may be amenable to therapeutic intervention.

慢性压力会对认知和情绪行为产生深远的负面影响，是神经精神疾病发展的主要危险因素。然而，慢性应激及其对神经元和突触功能的有害影响之间的分子联系仍然难以捉摸。在这里，我们结合体外和体内方法，证明慢性应激引发的 miR-186-5p 上调可能是此类变化的关键介质，导致突触功能障碍。我们的结果表明，在暴露于慢性应激的小鼠的前额皮质（PFC）和长期暴露于地塞米松的皮质神经元中，miR-186-5p的表达水平均增加。此外，病毒在幼鼠前额皮质中过度表达 miR-186-5p 会诱导焦虑和抑郁样行为。在体外或慢性应激小鼠模型中，通过延长糖皮质激素受体激活来上调 miR-186-5p，对谷氨酸能和 GABA 能突触传递产生不同的影响，导致兴奋/抑制失衡，从而导致神经元网络活动改变。在谷氨酸能突触中，我们观察到突触 AMPAR 和突触传递均减少，而 GABA 能突触传递则增强。这些变化可以在体外通过 miR-186-5p 抑制剂来挽救。总体而言，我们的结果在慢性糖皮质激素受体激活、miR-186-5p 上调和慢性应激诱导的突触变化之间建立了一种新的分子联系，这可能适合治疗干预。