CircFhit Modulates GABAergic Synaptic Transmission via Regulating the Parental Gene Fhit Expression in the Spinal Dorsal Horn in a Rat Model of Neuropathic Pain
作者机构：Neuroscience Program of Zhongshan School of Medicine and the Fifth Affiliated HospitalSun Yat-sen UniversityGuangzhou510080China Guangdong Province Key Laboratory of Brain Function and DiseaseSun Yat-sen UniversityGuangzhou510120China Department of Anesthesia and Pain MedicineGuangzhou First People’s HospitalGuangzhou510000China Department of PhysiologyXuzhou Medical UniversityXuzhou221004China Department of NeurologyThe Second Affiliated HospitalGuangzhou Medical UniversityGuangzhou510000China Guangdong Provincial Engineering Research Center of Molecular ImagingGuangdong Provincial Key Laboratory of Biomedical Imagingand Department of Interventional MedicineThe Fifth Affiliated HospitalSun Yat-sen UniversityZhuhai519000China The Affiliated Brain Hospital(Guangzhou Huiai Hospital)and School of Health ManagementGuangzhou Medical UniversityGuangzhou510182China Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired IntelligenceGuangzhou510000China
出 版 物：《Neuroscience Bulletin》 (神经科学通报（英文版）)
年 卷 期：2023年第39卷第6期
页 面：947-961页
核心收录：
学科分类：0710[理学-生物学] 07[理学] 1001[医学-基础医学(可授医学、理学学位)] 071006[理学-神经生物学]
基 金：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) the Fundamental Research Funds for the Central Universities(19ykpy44).
主 题：Chronic pain Neuropathic pain CircRNA Inhibitory transmission Epigenetic regulation
摘 要：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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