Aquaporin-4 Peptide Injection in Mice Induces Retinal and Optic Nerve Alterations That Simulate Those of Neuromyelitis Optica Spectrum Disorder.

PURPOSE

To investigate functional and structural changes in the retinas and optic nerves of mice immunized with an aquaporin-4 (AQP4) peptide, which was previously shown to induce paralysis mimicking human neuromyelitis optica spectrum disorder (NMOSD).

METHODS

Electroretinography and histological analyses were used to evaluate retinal function, and inflammatory cell infiltration or glial fibrillary acidic protein immunoreactivity in the retinas and optic nerves of AQP4-immunized mice. Additionally, the blood-retinal barrier function was assessed by Evans blue dye injection to measure in vivo retinal vascular permeability and by in vitro transendothelial electrical resistance using mouse primary retinal microvascular endothelial cells exposed to serum from AQP4-immunized mice.

RESULTS

AQP4 immunization led to a significant reduction in b-wave and scotopic threshold response amplitudes, indicating impaired inner retinal function. Histological analysis revealed inflammatory cell infiltration at the optic nerve head. Whole-mounted retinal glial fibrillary acidic protein immunoreactivity showed aberrant Müller cell activation, particularly in the juxtapapillary region. AQP4-immunized mice exhibited increased retinal Evans blue dye leakage and mouse retinal microvascular endothelial cells exhibited reduced transendothelial electrical resistance, indicating blood-retinal barrier disruption.

CONCLUSIONS

AQP4 immunization induced functional impairment, inflammatory cell infiltration, glial cell activation, and blood-retinal barrier disruption in the retinas and optic nerves in mice, which mimics human NMOSD-associated optic neuritis.

TRANSLATIONAL RELEVANCE

Along with the previously reported development of paralysis, this study indicates that AQP4 peptide-immunized mice can be considered an animal model of NMOSD and a powerful tool for further understanding the pathophysiology of NMOSD-associated optic neuritis and for assessing the efficacy of drugs in its treatment.