Activation of SNr GABA neurons drives liver-brain-eye axis dysfunction in hepatic encephalopathy.

Hepatic encephalopathy (HE) is frequently accompanied by visual dysfunction, yet the mechanisms underlying the liver-brain-eye axis remain unclear. We established mouse models of acute hepatic encephalopathy (AHE) using thioacetamide and chronic hepatic encephalopathy (CHE) using bile duct ligation, confirming hyperammonemia and visual impairment by electroretinogram (ERG) and visual evoked potentials (VEPs). Retinal analyses revealed preserved structure in AHE, whereas CHE induced significant thinning of the ganglion cell layer (GCL), inner nuclear layer (INL), and outer plexiform layer (OPL). Viral anterograde tracing identified aberrant activation of medial substantia nigra pars reticulata glutamate decarboxylase 2-positive (mSNr(GAD2)) projections to the superior colliculus (SC) under AHE conditions. Chemogenetic inhibition of this pathway restored retinal function, normalized visual signal transmission, and reduced retinal γ-aminobutyric acid (GABA) release. These findings identify SNr-SC signaling as a key neural mechanism driving liver-brain-eye axis dysfunction in HE.