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

Ting Xu ¹Zhen-Yu Li ¹Meng Liu ²Su-Bo Zhang ³Huan-Huan Ding ⁴Jia-Yan Wu ¹Su-Yan Lin ⁵Jun Liu ⁵Jia-You Wei ⁶Xue-Qin Zhang ⁷Wen-Jun Xin⁸

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作者信息

1. Neuroscience Program of Zhongshan School of Medicine and the Fifth Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,China;Guangdong Province Key Laboratory of Brain Function and Disease,Sun Yat-sen University,Guangzhou 510120,China
2. Department of Anesthesia and Pain Medicine,Guangzhou First People's Hospital,Guangzhou 510000,China
3. Neuroscience Program of Zhongshan School of Medicine and the Fifth Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,China
4. Department of Physiology,Xuzhou Medical University,Xuzhou 221004,China
5. Department of Neurology,The Second Affiliated Hospital,Guangzhou Medical University,Guangzhou 510000,China
6. Neuroscience Program of Zhongshan School of Medicine and the Fifth Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,China;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
7. The Affiliated Brain Hospital(Guangzhou Huiai Hospital)and School of Health Management,Guangzhou Medical University,Guangzhou 510182,China
8. Neuroscience Program of Zhongshan School of Medicine and the Fifth Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,China;Guangdong Province Key Laboratory of Brain Function and Disease,Sun Yat-sen University,Guangzhou 510120,China;Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence,Guangzhou 510000,China
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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 synap-tic 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 Ⅱphosphorylation and H2B monoubiquitination by recruit-ing CDK9 and RNF40 to the Fhit intron.In summary,we revealed that the exon-intron circFhit contributes to GABAe-rgic neuron-mediated NK1R+neuronal hyperexcitation and neuropathic pain via regulating Fhit in cis.

Key words

Chronic pain/Neuropathic pain/CircRNA/Inhibitory transmission/Epigenetic regulation

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基金项目

National Natural Science Foundation of China(319700936)

National Natural Science Foundation of China(81801103)

National Natural Science Foundation of China(81901127)

National Natural Science Foundation of China(82101307)

Science and Technology Program of Guangdong(2018B030334001)

Natural Science Foundation of Guangdong(2019A1515010871)

Natural Science Foundation of Guangdong(2019A1515010645)

Natural Science Foundation of Guangdong(2022A1515010414)

Guangzhou Science and Technology Plan Project(201803010006)

Natural Science Foundation of Jiangsu(BK20210904)

Fundamental Research Funds for the Central Universities(19ykpy44)

出版年

2023

神经科学通报(英文版)

中国科学院上海生命科学研究院

神经科学通报(英文版)

CSTPCDCSCD

影响因子：0.741

ISSN：1673-7067

参考文献量39

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