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.