Dynamic characterization of pathological and functional deterioration in a mouse model of optic neuritis related to neuromyelitis optica spectrum disorder

Abstract

Neuromyelitis optica spectrum disorder-related optic neuritis involves various cellular responses to inflammation and degeneration. In most patients, the primary mechanism underlying neuromyelitis optica spectrum disorder-related optic neuritis is the interaction of aquaporin-4 antibodies with the aquaporin-4 protein present on astrocytes within posterior optic nerve. This binding subsequently initiates a cascade of events leading to secondary demyelination of the optic nerve, ultimately culminating in optic nerve degeneration. Earlier studies on this disorder primarily used systemic-induced animal models, which often require prior activation of a systemic immune response. This can result in primary demyelination of the optic nerve, complicating the interpretation of experimental results. Such methodologies hinder the ability to isolate immune responses triggered by specific antibodies. Additionally, the lack of a detailed profile of disease progression over time limits our capacity to identify potential intervention windows. Therefore, constructing a targeted optic neuritis animal model induced by specific antibodies and elucidate the disease progression arecrucial for exploring the mechanisms underlying neuromyelitis optica spectrum disorder- related optic neuritis. In this study, specific antibodies against aquaporin-4 were precisely injected into the retrobulbar optic nerve of mice to induce a targeted inflammatory response in the posterior optic nerve, resulting in a more representative mouse model of neuromyelitis optica spectrum disorder-related optic neuritis than current models. The progression of the disease was then dynamically observed from both histological and functional perspectives over the course of 1 month following the induction of inflammation. By the first week, astrocytes were damaged, as evidenced by the loss of aquaporin-4 and glial fibrillary acidic protein, the activation of microglia, and the upregulation of microglia-related cytokines, including tumor necrosis factor, interleukin-6, interleukin-1β, C-X-C motif ligand 10, and brain-derived neurotrophic factor. Starting from the second week, there were signs of optic nerve demyelination and significant damage to axonal fibers and retinal ganglion cell bodies. Visual-evoked potentials and dark adaptation threshold responses in electroretinogram both indicated dysfunction in the visual pathway and retina, while optical coherence tomography revealed thinning of the retinal nerve fiber layer in live mice. In summary, in this study we conducted a dynamic exploration of the occurrence and progression of neuromyelitis optica spectrum disorder-related optic neuritis triggered by specific antibodies. Our results show pathological changes at various stages and correlate histological and molecular alterations with in vivo structural and functional deterioration. The findings from this study lay an important foundation for further research on neuromyelitis optica spectrum disorder-related optic neuritis.