Augmentation of 2-arachidonoylglycerol signaling in astrocytes maintains synaptic functionality by regulation of miRNA-30b.
Augmentation of 2-arachidonoylglycerol signaling in astrocytes maintains synaptic functionality by regulation of miRNA-30b.
复制标题
星形胶质细胞中 2-花生四烯酰甘油信号传导的增强可通过调节 miRNA-30b 维持突触功能。
DOI：
10.1016/j.expneurol.2022.114292
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发表时间：
2023
影响因子：
5.3
通讯作者：
Chen,Chu
中科院分区：
文献类型：
--
作者：
Zhu,Dexiao;Zhang,Jian;Gao,Fei;Hu,Mei;Hashem,Jack;Chen,Chu
2-花生四烯酰甘油（2-AG），最丰富的内源性大麻素，显示抗炎和神经保护特性。在神经退行性疾病的动物模型中，通过单酰基甘油脂肪酶（MAGL）（脑中降解2-AG的关键酶）的失活抑制2-AG降解，可减轻神经病理学并改善突触和认知功能。特别地，通过mgll的遗传缺失而使MAGL的整体失活增强海马长时程增强（LTP）和海马依赖性学习和记忆。然而，我们对MAGL慢性失活增强突触活性的分子机制的理解仍然有限。在这里，我们提供的证据表明，MAGL的药理学失活抑制海马表达的miR-30 b，一个小的非编码microRNA，并上调其目标的表达，包括肝配蛋白B型受体2（ephB 2），sirtuin 1（sirt 1），和谷氨酸离子型受体AMPA型亚基2（GluA 2）。重要的是，通过MAGL失活来抑制miR-30 b并增加其靶点主要是由于抑制星形胶质细胞而不是神经元中的2-AG代谢。星形胶质细胞中MAGL的失活可防止海马中miR-30 b过表达诱导的突触传递和长时程增强（LTP）损伤。通过MAGL失活抑制miR-30 b表达显然与2-AG信号传导增强相关，因为2-AG诱导miR-30 b表达的剂量依赖性降低。2-AG或MAGL失活抑制miR-30 b的表达不是通过CB 1 R介导的，而是通过过氧化物酶体增殖物激活受体γ（PPARγ）介导的。这进一步得到以下结果的支持：MAGL失活诱导的miR-30 b下调和其靶点上调被PPARγ拮抗作用减弱，但被PPARγ激动剂模拟。此外，我们观察到2-AG诱导的miR-30 b表达减少是通过NF-κ B信号转导介导的。我们的研究提供了证据表明，星形胶质细胞中的2-AG信号通过调节miR-30 b表达在维持海马突触功能完整性方面起着重要作用。
2-Arachidonoylglycerol (2-AG), the most abundant endocannabinoid, displays anti-inflammatory and neuroprotective properties. Inhibition of 2-AG degradation by inactivation of monoacylglycerol lipase (MAGL), a key enzyme degrading 2-AG in the brain, alleviates neuropathology and improves synaptic and cognitive functions in animal models of neurodegenerative diseases. In particular, global inactivation of MAGL by genetic deletion of mgll enhances hippocampal long-term potentiation (LTP) and hippocampus-dependent learning and memory. However, our understanding of the molecular mechanisms by which chronic inactivation of MAGL enhances synaptic activity is still limited. Here, we provide evidence that pharmacological inactivation of MAGL suppresses hippocampal expression of miR-30b, a small non-coding microRNA, and upregulates expression of its targets, including ephrin type-B receptor 2 (ephB2), sirtuin1 (sirt1), and glutamate ionotropic receptor AMPA type subunit 2 (GluA2). Importantly, suppression of miR-30b and increase of its targets by inactivation of MAGL result primarily from inhibition of 2-AG metabolism in astrocytes, rather than in neurons. Inactivation of MAGL in astrocytes prevents miR-30b overexpression-induced impairments in synaptic transmission and long-term potentiation (LTP) in the hippocampus. Suppression of miR-30b expression by inactivation of MAGL is apparently associated with augmentation of 2-AG signaling, as 2-AG induces a dose-dependent decrease in expression of miR-30b. 2-AG- or MAGL inactivation-suppressed expression of miR-30b is not mediated via CB1R, but by peroxisome proliferator-activated receptor γ (PPARγ). This is further supported by the results showing that MAGL inactivation-induced downregulation of miR-30b and upregulation of its targets are attenuated by antagonism of PPARγ, but mimicked by PPARγ agonists. In addition, we observed that 2-AG-induced reduction of miR-30b expression is mediated via NF-kB signaling. Our study provides evidence that 2-AG signaling in astrocytes plays an important role in maintaining the functional integrity of synapses in the hippocampus by regulation of miR-30b expression.