Upregulation of HDAC3 mediates behavioral impairment in the bile duct ligation model of hepatic encephalopathy.

Hepatic encephalopathy (HE), an outcome of chronic liver disease is characterized by behavioral impairments. The present study investigated the role of HDAC-mediated transcriptional regulation causing behavioral impairments in the bile duct ligation (BDL) model of HE. Post-BDL surgery in rats, dynamic alterations in liver function tests, liver morphology were observed. In BDL rats, histological staining in brain demonstrated reduced neuronal viability and warped neuronal architecture. Additionally, BDL animals showed impaired spatial learning, memory, and increased anxiety in the open field, Barnes maze, and Y maze tests. Further, the Golgi cox staining revealed a significantly altered spine density and spine clustering patterns of granular neuron in dentate gyrus of BDL rats. Concordantly, a significant downregulation of memory encoding genes was also observed in BDL rats that may account for aberrant behavior. Molecular analysis of modifiers, such as HDAC, showed significant changes in the expression of HDAC3 and HDAC6 in both the cortex and hippocampus of BDL rats. Upregulation of HDAC3 promoted its localization on the promoter of genes like c-Fos, NPAS4, Arc, and others, likely causing their decreased expression. Our findings suggest that increased HDAC3 activity downregulates key synaptic plasticity and memory-related genes, potentially driving neurobehavioral changes in BDL rats.