Department of Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, China.
Department of 1st Clinical Medicine, China Medical University, Shenyang, China.
J Neuroinflammation. 2021 Jan 6;18(1):17. doi: 10.1186/s12974-020-02064-0.
FMRP is a selective mRNA-binding protein that regulates protein synthesis at synapses, and its loss may lead to the impairment of trace fear memory. Previously, we found that FMRP levels in the hippocampus of rats with post-traumatic stress disorder (PTSD) were decreased. However, the mechanism underlying these changes remains unclear.
Forty-eight male Sprague-Dawley rats were randomly divided into four groups. The experimental groups were treated with the single-prolonged stress (SPS) procedure and injected with a lentivirus-mediated inhibitor of miR-142-5p. Behavior test as well as morphology and molecular biology experiments were performed to detect the effect of miR-142 downregulation on PTSD, which was further verified by in vitro experiments.
We found that silence of miRNA-142 (miR-142), an upstream regulator of FMRP, could alleviate PTSD-like behaviors of rats exposed to the SPS paradigm. MiR-142 silence not only decreased the levels of proinflammatory mediators, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α, but also increased the expressive levels of synaptic proteins including PSD95 and synapsin I in the hippocampus, which was one of the key brain regions associated with PTSD. We further detected that miR-142 silence also downregulated the transportation of nuclear factor kappa-B (NF-κB) into the nuclei of neurons and might further affect the morphology of neurons.
The results revealed miR-142 downregulation could alleviate PTSD-like behaviors through attenuating neuroinflammation in the hippocampus of SPS rats by binding to FMRP.
FMRP 是一种选择性的 mRNA 结合蛋白,可调节突触处的蛋白质合成,其缺失可能导致痕迹恐惧记忆受损。先前,我们发现创伤后应激障碍(PTSD)大鼠海马中的 FMRP 水平降低。然而,这些变化的机制尚不清楚。
48 只雄性 Sprague-Dawley 大鼠随机分为四组。实验组接受单一延长应激(SPS)程序处理,并注射慢病毒介导的 miR-142-5p 抑制剂。通过行为测试以及形态学和分子生物学实验来检测 miR-142 下调对 PTSD 的影响,进一步通过体外实验进行验证。
我们发现,作为 FMRP 上游调控因子的 miRNA-142(miR-142)沉默可减轻 SPS 范式暴露的大鼠 PTSD 样行为。miR-142 沉默不仅降低了促炎介质(如白细胞介素-1β、白细胞介素-6 和肿瘤坏死因子-α)的水平,还增加了海马中包括 PSD95 和突触小体 I 在内的突触蛋白的表达水平,海马是与 PTSD 相关的关键脑区之一。我们进一步检测到,miR-142 沉默还下调了核因子 kappa-B(NF-κB)向神经元核内的运输,并可能进一步影响神经元的形态。
研究结果表明,miR-142 沉默通过与 FMRP 结合减轻 SPS 大鼠海马中的神经炎症,从而缓解 PTSD 样行为。