Role of hippocampal circKcnk9 in visceral hypersensitivity and anxiety comorbidity of Irritable Bowel Syndrome

Abstract Irritable bowel syndrome (IBS) is a prevalent functional disease. However, its molecular and pathological mechanisms are poorly understood. In this study, neonatal colorectal distension induced visceral hypersensitivity and anxiety comorbidity. The expression of hippocampal circKcnk9, a novel circRNA we termed, was increased significantly in IBS-like rats. Interesting, CA1 shcircKcnk9 treatment inhibited LTP and alleviated visceral hypersensitivity and anxiety in IBS-like rats while overexpression of CA1 circKcnk9 induced LTP, visceral hypersensitivity and anxiety in controls. Then, several experiments indicated that increased CA1 circKcnk9 acts as miR-124-3p sponge, which results in the inhibiting effect of miR-124-3p on gene silencing. There was a negative correlation between circKcnk9 and miR-124-3p. As expected, CA1 administration of agomiR-124-3p decreased CA1 LTP, visceral hypersensitivity and anxiety in IBS-like rats. In contrast, CA1 treatment with antagomiR-124-3p induced LTP, visceral hypersensitivity and anxiety in controls. Furthermore, bioinformatics analysis and experimental data showed EZH2 is a target gene of circKcnk9/miR-124-3p and increased EZH2 expression is involved in visceral hypersensitivity and anxiety of IBS-like rats by enhancing hippocampal synaptic plasticity. In conclusion, early life stress induces increased expression of circKcnk9 in the CA1 of IBS-like rats. Increased circKcnk9 ensuing regulates the synaptic transmission and enhances LTP, leading to visceral hypersensitivity and anxiety comorbidity in IBS-like rats. The underlying signaling pathway of circKcnk9 is miR124-3p/EZH2. Increased circKcnk9 reinforces its sponge for miR124-3p, strongly suppresses miR124-3p activity, resulting in increased expression level of target gene EZH2. The study provides a new epigenetic mechanism of visceral hypersensitivity and anxiety comorbidity in IBS-like rats.