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., 2023 · DOI: https://doi.org/10.1007/s12264-022-01014-5 · Published: January 13, 2023

Simple Explanation

This study investigates the role of circFhit, a circular RNA, in neuropathic pain. It finds that circFhit, expressed in GABAergic neurons, reduces inhibitory synaptic transmission in the spinal dorsal horn, contributing to neuropathic pain. The research further reveals that circFhit decreases GAD65 expression and induces hyperexcitation in NK1R+ neurons. This is achieved by promoting the expression of its parental gene, Fhit. The study uncovers the mechanism by which circFhit binds to the intronic region of Fhit, forming a complex that recruits CDK9 and RNF40, leading to Pol II phosphorylation and H2B monoubiquitination. This, in turn, regulates Fhit expression and contributes to neuropathic pain.

Study Duration

Not specified

Participants

Male Sprague-Dawley rats (180–220 g)

Evidence Level

Not specified

Key Findings

1
CircFhit, an exon-intron circRNA, is upregulated in the spinal dorsal horn in a neuropathic pain model and contributes to neuropathic pain following spared nerve injury (SNI).
2
CircFhit enhances the activity of NK1R+ neurons by reducing GABAergic synaptic transmission, impacting the microcircuit loop from GABAergic neurons to NK1R+ neurons.
3
After SNI, circFhit decreases the expression of GAD65 via regulating the parental gene Fhit, with circFhit increasing phosphorylated Pol II and monoubiquitylated H2B on the circFhit-binding region of the Fhit gene.

Research Summary

The study elucidated the role of exon-intron circRNA, circFhit, as a critical regulator in the pathogenesis of neuropathic pain induced by peripheral nerve injury. CircFhit modulation of FHIT expression contributed to the reduction of GABAergic inhibitory neurotransmitter synthesis and the dorsal horn NK1R+ neuronal hyperexcitation and neuropathic pain following SNI. The exon-intron circFhit in GABAergic inhibitory neurons regulates the expression of the parental Fhit gene in cis and subsequently contributes to NK1R+ neuronal hyperexcitation and neuropathic pain induced by nerve injury.

Practical Implications

Targeted Therapies

CircFhit represents a novel target for developing effective treatments for neuropathic pain by modulating GABAergic neurotransmission.

Epigenetic Regulation

Understanding the epigenetic mechanisms by which circFhit regulates Fhit expression can provide insights into other neurological disorders.

Microcircuitry Modulation

Interventions aimed at restoring the balance in the GABAergic-NK1R+ neuronal microcircuit may alleviate neuropathic pain.

Study Limitations

1
The study is limited to a rat model of neuropathic pain, and the findings may not directly translate to human conditions.
2
The specific function of FHIT in regulating ion channels and inflammatory cytokines in the context of neuropathic pain requires further investigation.
3
The study does not fully explore the potential involvement of other circRNAs or non-coding RNAs in the development of neuropathic pain.

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