Alteration of twinfilin1 expression underlies opioid withdrawal-induced remodeling of actin cytoskeleton at synapses and formation of aversive memory

Alteration of twinfilin1 expression underlies opioid withdrawal-induced remodeling of actin cytoskeleton at synapses and formation of aversive memory

Abstract

Exposure to drugs of abuse induces alterations of dendritic spine morphology and density that has been proposed to be a cellular basis of long-lasting addictive memory and heavily depend on remodeling of its underlying actin cytoskeleton by the actin cytoskeleton regulators. However, the actin cytoskeleton regulators involved and the specific mechanisms whereby drugs of abuse alter their expression or function are largely unknown. Twinfilin (Twf1) is a highly conserved actin-depolymerizing factor that regulates actin dynamics in organisms from yeast to mammals. Despite abundant expression of Twf1 in mammalian brain, little is known about its importance for brain functions such as experience-dependent synaptic and behavioral plasticity. Here we show that conditioned morphine withdrawal (CMW)-induced synaptic structure and behavior plasticity depends on downregulation of Twf1 in the amygdala of rats. Genetically manipulating Twf1 expression in the amygdala bidirectionally regulates CMW-induced changes in actin polymerization, spine density and behavior. We further demonstrate that downregulation of Twf1 is due to upregulation of miR101a expression via a previously unrecognized mechanism involving CMW-induced increases in miR101a nuclear processing via phosphorylation of MeCP 2 at Ser421. Our findings establish the importance of Twf1 in regulating opioid-induced synaptic and behavioral plasticity and demonstrate its value as a potential therapeutic target for the treatment of opioid addiction. Data availability

The data that support the findings of this study are available on request from the corresponding author. Acknowledgements

This research was supported by grants 81130087, 81671322 (to J-GL) and 81773710 (to Y-JW) from National Natural Science Foundation of China, by grant 2015CB553502 (to J-GL) from the Ministry of Sciences and Technology of China, by grant 2017334 (to Y-JW) from the Youth Innovation Promotion Association of the Chinese Academy of Sciences. Author information

> These authors contributed equally: Y-J Wang, C Yu, W-W Wu

Affiliations

> Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

Yu-Jun Wang, Chuan Yu, Wei-Wei Wu, Yun-Yue Ju, Yao Liu, Jian-Dong Long, Gui-Ying Zan, Le-Sha Zhang, Jing-Rui Chai & Jing-Gen Liu

Department of Neurobiology and Acupuncture Research, The Third Clinical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, China

Contributions

J-GL, Y-JW, and ZC designed the experiment. Y-JW, CY, W-WW, YYJ, and YL performed the experiments with the assistance of J-DL, G-YZ, X-YW, L-SZ, J-RC Statistical data analysis was performed by Y-JW, CY, and W-WW. This manuscript was written by Y-JW and CX and was revised by J-GL and ZC. Corresponding authors

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Cite this article

Wang, YJ., Yu, C., Wu, WW. et al. Alteration of twinfilin1 expression underlies opioid withdrawal-induced remodeling of actin cytoskeleton at synapses and formation of aversive memory. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01111-3

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