Selective Intrinsically Photosensitive Retinal Ganglion Cells Ablation Regulates Myopia Development Through the Choroid/MAPK Pathway.

Abstract

Purpose: This study investigates the role of selective ablation of intrinsically photosensitive retinal ganglion cells (ipRGCs) in regulating axial length (AL) and scleral remodeling during myopia progression.

Methods: Three-week-old pigmented guinea pigs were randomly assigned to five experimental groups, with form-deprivation myopia (FDM) models receiving intravitreal melanopsin-saporin (MEL-SAP) injections. Molecular analyses (Western blot, RT-qPCR) quantified expression of retina-, choroid-, and sclera-related factors. Structural changes were assessed via immunohistochemistry, optical coherence tomography (OCT; choroidal/scleral thickness), and Masson's trichrome staining (scleral collagen organization).

Results: In FDM models, melanopsin expression was elevated. MEL-SAP injection shortened the AL and slowed the progression of late-stage myopia. This treatment attenuated AL elongation and delayed refractive progression in FDM+MEL-SAP groups versus FDM alone. Molecular analyses indicated suppression of FDM-induced scleral remodeling markers and choroidal hypoxia indicators following selective ipRGCs ablation. Activation of extracellular regulated kinase (ERK) by the specific agonist Ro67-7476 reversed the effects of ipRGC ablation, demonstrating the functional involvement of microtubule-associated protein kinase (MAPK)/ERK signaling in mediating the anti-myopic effects. Choroidal perfusion experiments supported selective ipRGC ablation's primary action through the retinal-choroidal-scleral(RCS) axis.

Conclusion: Collectively, our results reveal that the ipRGCs mediates the effects of choroid/MAPK pathway on AL, providing a refined understanding of retinal mechanisms and identifying a potential therapeutic target for myopia.