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CircFhit Modulates GABAergic Synaptic Transmission via Regulating the Parental Gene Fhit Expression in the Spinal Dorsal Horn in a Rat Model of Neuropathic Pain

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Abstract

Effective treatments for neuropathic pain are lacking due to our limited understanding of the mechanisms. The circRNAs are mainly enriched in the central nervous system. However, their function in various physiological and pathological conditions have yet to be determined. Here, we identified circFhit, an exon-intron circRNA expressed in GABAergic neurons, which reduced the inhibitory synaptic transmission in the spinal dorsal horn to mediate spared nerve injury-induced neuropathic pain. Moreover, we found that circFhit decreased the expression of GAD65 and induced hyperexcitation in NK1R+ neurons by promoting the expression of its parental gene Fhit in cis. Mechanistically, circFhit was directly bound to the intronic region of Fhit, and formed a circFhit/HNRNPK complex to promote Pol II phosphorylation and H2B monoubiquitination by recruiting CDK9 and RNF40 to the Fhit intron. In summary, we revealed that the exon-intron circFhit contributes to GABAergic neuron-mediated NK1R+ neuronal hyperexcitation and neuropathic pain via regulating Fhit in cis.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (319700936, 81801103, 81901127, and 82101307), the Science and Technology Program of Guangdong (2018B030334001), the Natural Science Foundation of Guangdong (2019A1515010871, 2019A1515010645, and 2022A1515010414), the Guangzhou Science and Technology Plan Project (201803010006), the Natural Science Foundation of Jiangsu (BK20210904), and the Fundamental Research Funds for the Central Universities (19ykpy44). We thank Prof. Zhi-Cheng Dong for helping with the experiment on nuclear run-ons.

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Author notes

  1. Ting Xu, Zhen-Yu Li, and Meng Liu contributed equally to this work.

Authors and Affiliations

  1. Neuroscience Program of Zhongshan School of Medicine and the Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China

    Ting Xu, Zhen-Yu Li, Su-Bo Zhang, Jia-Yan Wu, Jia-You Wei & Wen-Jun Xin

  2. Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-sen University, Guangzhou, 510120, China

    Ting Xu, Zhen-Yu Li, Jia-Yan Wu & Wen-Jun Xin

  3. Department of Anesthesia and Pain Medicine, Guangzhou First People’s Hospital, Guangzhou, 510000, China

    Meng Liu

  4. Department of Physiology, Xuzhou Medical University, Xuzhou, 221004, China

    Huan-Huan Ding

  5. Department of Neurology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510000, China

    Su-Yan Lin & Jun Liu

  6. Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, China

    Jia-You Wei

  7. The Affiliated Brain Hospital (Guangzhou Huiai Hospital) and School of Health Management, Guangzhou Medical University, Guangzhou, 510182, China

    Xue-Qin Zhang

  8. Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, 510000, China

    Wen-Jun Xin

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  1. Ting Xu
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Xu, T., Li, ZY., Liu, M. et al. CircFhit Modulates GABAergic Synaptic Transmission via Regulating the Parental Gene Fhit Expression in the Spinal Dorsal Horn in a Rat Model of Neuropathic Pain. Neurosci. Bull. 39, 947–961 (2023). https://doi.org/10.1007/s12264-022-01014-5

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