Circular RNA Tmcc1 improves astrocytic glutamate metabolism and spatial memory via NF-κB and CREB signaling in a bile duct ligation mouse model: transcriptional and cellular analyses.

Abstract

BACKGROUND: Hepatic encephalopathy-induced hyperammonemia alters astrocytic glutamate metabolism in the brain, which is involved in cognitive decline. To identify specific therapeutic strategies for the treatment of hepatic encephalopathy, various molecular signaling studies, such as non-coding RNA functional study, have been conducted. However, despite several reports of circular RNAs (circRNAs) in the brain, few studies of circRNAs in hepatic encephalopathy-induced neuropathophysiological diseases have been conducted. METHODS: In this study, we performed RNA sequencing to identify whether the candidate circRNA cirTmcc1 is specifically expressed in the brain cortex in a bile duct ligation (BDL) mouse model of hepatic encephalopathy. RESULTS: Based on transcriptional and cellular analysis, we investigated the circTmcc1-dysregulation-induced changes in the expression of several genes that are associated with intracellular metabolism and astrocyte function. We found that the circTmcc1 binds with the NF-κB p65-CREB transcriptional complex and regulates the expression of the astrocyte transporter EAAT2. Furthermore, circTmcc1 contributed to the secretion of proinflammatory mediators and glutamate metabolism in astrocytes and subsequently modulated an improvement in spatial memory by mediating neuronal synaptic plasticity. CONCLUSIONS: Thus, circTmcc1 may be a promising circRNA candidate for targeted interventions to prevent and treat the neuropathophysiological complications that occur due to hepatic encephalopathy.