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针刺通过调控小胶质细胞 PI3K 通路的表观遗传修饰改善创伤后应激障碍模型大鼠的学习记忆能力。

Acupuncture improves learning and memory ability of posttraumatic stress disorder model rats through epigenetic regulation of microglial phosphatidylinositol 3-kinase pathway.

机构信息

College of Traditional Chinese Medicine, Hainan Medical University, Haikou, Hainan, China.

College of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.

出版信息

Technol Health Care. 2023;31(S1):409-421. doi: 10.3233/THC-236035.

DOI:10.3233/THC-236035
PMID:37066940
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10200193/
Abstract

BACKGROUND

Microglia express phosphatidylinositol 3-kinase (PI3K) has been implicated in the induction and maintenance of long-term potentiation (LTP) and in hippocampal synaptic plasticity. However, there are few studies on the interference of PI3K signal pathway in microglia.

OBJECTIVE

The study goal is to gain a better understanding of the mechanism by which EA affects synapses provides insights into how electroacupuncture (EA) modulates synaptic plasticity in learning and memory.

METHODS

Rat models of posttraumatic stress disorder (PTSD) were used to explore the effects of EA on microglial PI3K pathway, brain-derived neurotrophic factor (BDNF) and LTP, and the target and mechanism underlying the effects of EA on PI3K from the perspective of protein ubiquitination.

RESULTS

EA induced microglial BDNF expression by activating the PI3K-AKT pathway, thereby facilitating LTP and synaptic plasticity. EA inhibited lincRNA 02023 to rescue the binding of WWP2 to PTEN, thereby promoting PTEN ubiquitination and degradation.

CONCLUSION

The mechanism of EA improving the learning and memory ability of PTSD rats may be that it can promote the competitive combination of WWP2 and PTEN by inhibiting Linc RNA02023, and then lead to microglial PI3K and its pathway activation, BDNF up-regulation, and finally induce LTP and repair damaged synaptic plasticity.

摘要

背景

小胶质细胞表达的磷酸肌醇 3-激酶(PI3K)已被牵连在长时程增强(LTP)的诱导和维持以及海马突触可塑性中。然而,关于小胶质细胞中 PI3K 信号通路的干扰的研究较少。

目的

本研究旨在深入了解 EA 影响突触的机制,为电针(EA)如何调节学习和记忆中的突触可塑性提供思路。

方法

使用创伤后应激障碍(PTSD)大鼠模型,从蛋白质泛素化的角度探讨 EA 对小胶质细胞 PI3K 通路、脑源性神经营养因子(BDNF)和 LTP 的影响,以及 EA 对 PI3K 影响的靶点和机制。

结果

EA 通过激活 PI3K-AKT 通路诱导小胶质细胞 BDNF 表达,从而促进 LTP 和突触可塑性。EA 抑制 lincRNA 02023 以挽救 WWP2 与 PTEN 的结合,从而促进 PTEN 泛素化和降解。

结论

EA 改善 PTSD 大鼠学习记忆能力的机制可能是通过抑制 Linc RNA02023,促进 WWP2 和 PTEN 的竞争性结合,进而导致小胶质细胞 PI3K 及其通路的激活、BDNF 的上调,最终诱导 LTP 和修复受损的突触可塑性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ce4/10200193/5c408f63cc32/thc-31-thc236035-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ce4/10200193/6bb779cf28d0/thc-31-thc236035-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ce4/10200193/50699529292d/thc-31-thc236035-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ce4/10200193/fd27dc8ce431/thc-31-thc236035-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ce4/10200193/819f80ec1846/thc-31-thc236035-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ce4/10200193/6479bea7bfac/thc-31-thc236035-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ce4/10200193/5c408f63cc32/thc-31-thc236035-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ce4/10200193/6bb779cf28d0/thc-31-thc236035-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ce4/10200193/50699529292d/thc-31-thc236035-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ce4/10200193/fd27dc8ce431/thc-31-thc236035-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ce4/10200193/819f80ec1846/thc-31-thc236035-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ce4/10200193/6479bea7bfac/thc-31-thc236035-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ce4/10200193/5c408f63cc32/thc-31-thc236035-g006.jpg

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本文引用的文献

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Neuroprotective Effect of Acupuncture against Single Prolonged Stress-Induced Memory Impairments and Inflammation in Rat Brain via Modulation of Brain-Derived Neurotrophic Factor Expression.针刺通过调节脑源性神经营养因子表达对大鼠单次长时间应激诱导的记忆损伤和脑内炎症的神经保护作用。
Evid Based Complement Alternat Med. 2022 Feb 23;2022:4430484. doi: 10.1155/2022/4430484. eCollection 2022.
2
Efficacy and Underlying Mechanism of Acupuncture in the Treatment of Posttraumatic Stress Disorder: A Systematic Review of Animal Studies.针刺治疗创伤后应激障碍的疗效及潜在机制:动物研究的系统评价
J Clin Med. 2021 Apr 8;10(8):1575. doi: 10.3390/jcm10081575.
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Synaptic elimination by microglia and disturbed higher brain functions.
小胶质细胞介导的突触消除与高级脑功能障碍
Neurochem Int. 2021 Jan;142:104901. doi: 10.1016/j.neuint.2020.104901. Epub 2020 Nov 9.
4
Electroacupuncture ameliorates post-traumatic stress disorder in rats via a mechanism involving the BDNF-TrkB signaling pathway.电针对大鼠创伤后应激障碍的改善作用涉及 BDNF-TrkB 信号通路。
Cell Mol Biol (Noisy-le-grand). 2020 Jun 5;66(3):165-170.
5
Epigenetic regulation of microglial phosphatidylinositol 3-kinase pathway involved in long-term potentiation and synaptic plasticity in rats.大鼠长时程增强和突触可塑性相关的小胶质细胞磷脂酰肌醇 3-激酶途径的表观遗传调控。
Glia. 2020 Mar;68(3):656-669. doi: 10.1002/glia.23748. Epub 2019 Nov 8.
6
Study on the mechanism of TMRK electroacupuncture in repairing synaptic plasticity in amygdala and hippocampus to relieve fear memory in PTSD rats.经皮穴位电刺激修复创伤后应激障碍大鼠杏仁核和海马突触可塑性以减轻恐惧记忆的机制研究
Technol Health Care. 2019;27(S1):425-443. doi: 10.3233/THC-199038.
7
WWP2 is a physiological ubiquitin ligase for phosphatase and tensin homolog (PTEN) in mice.WWP2 是一种在小鼠中针对磷酸酶和张力蛋白同系物(PTEN)的生理泛素连接酶。
J Biol Chem. 2018 Jun 8;293(23):8886-8899. doi: 10.1074/jbc.RA117.001060. Epub 2018 Apr 23.
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Microglia-Mediated Synapse Loss in Alzheimer's Disease.阿尔茨海默病中的小胶质细胞介导的突触丢失。
J Neurosci. 2018 Mar 21;38(12):2911-2919. doi: 10.1523/JNEUROSCI.1136-17.2017.
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Noncoding RNAs: Stress, Glucocorticoids, and Posttraumatic Stress Disorder.非编码 RNA:应激、糖皮质激素与创伤后应激障碍。
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Current Status of Animal Models of Posttraumatic Stress Disorder: Behavioral and Biological Phenotypes, and Future Challenges in Improving Translation.创伤后应激障碍动物模型的现状:行为和生物学表型,以及改善转化的未来挑战。
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