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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

 Ting Xu1,2 · Zhen‑Yu Li1,2 · Meng Liu3  · Su‑Bo Zhang1  · Huan‑Huan Ding4  · Jia‑Yan Wu1,2 · Su‑Yan Lin5  · Jun Liu5  · Jia‑You Wei1,6 · Xue‑Qin Zhang7  · Wen‑Jun Xin1,2,8
1 Neuroscience Program of Zhongshan School of Medicine and the Fifth Afliated Hospital, Sun Yat-sen University, Guangzhou 510080, China 
2 Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-sen University, Guangzhou 510120, China 
3 Department of Anesthesia and Pain Medicine, Guangzhou First People’s Hospital, Guangzhou 510000, China 
4 Department of Physiology, Xuzhou Medical University, Xuzhou 221004, China 5 Department of Neurology, The Second Afliated Hospital, Guangzhou Medical University, Guangzhou 510000, China 
6 Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Afliated Hospital, Sun Yat-sen University, Zhuhai 519000, China 
7 The Afliated Brain Hospital (Guangzhou Huiai Hospital) and School of Health Management, Guangzhou Medical University, Guangzhou 510182, China 
8 Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou 510000, China

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.


Keywords
Chronic pain; Neuropathic pain; CircRNA; Inhibitory transmission; Epigenetic regulation