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

## TL;DR

This study reveals that overactive brain neurons link liver disease to vision problems, offering a new understanding of how liver failure affects the brain and eyes.

## Contribution

The study identifies a specific brain pathway responsible for liver-brain-eye dysfunction in hepatic encephalopathy.

## Key findings

- Aberrant activation of mSNrGAD2 neurons was observed in acute hepatic encephalopathy.
- Chemogenetic inhibition of the mSNrGAD2-SC pathway restored retinal function and reduced GABA release.
- Chronic hepatic encephalopathy caused retinal layer thinning, unlike acute cases.

## Abstract

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 (mSNrGAD2) 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.

•Viral anterograde tracing with TRAP and GAD2-Cre mice showed SNr activation in AHE•Chemogenetic inhibition of the mSNrGAD2-SC pathway alleviated visual dysfunction•Aberrant mSNrGAD2-SC activation underlies the liver-brain-eye axis in HE

Viral anterograde tracing with TRAP and GAD2-Cre mice showed SNr activation in AHE

Chemogenetic inhibition of the mSNrGAD2-SC pathway alleviated visual dysfunction

Aberrant mSNrGAD2-SC activation underlies the liver-brain-eye axis in HE

Molecular physiology; Molecular neuroscience; Neuroanatomy