Purpose: Retinal ganglion cells (RGCs) transmit visual information to the brain and are selectively affected in glaucoma, a neurodegenerative disease caused by increased intraocular pressure (IOP) leading to vision loss. Not all RGC subtypes are equally vulnerable; thus, this study aimed to comprehensively analyze the differential loss of RGC subtypes using a rat model of chronic glaucoma. Methods: A chronic glaucoma model was established by cauterizing three episcleral veins in rat eyes. IOP was measured using an applanation tonometer, and after 40 days animals were euthanized. Whole-mount retinas were immunostained. RGCs were labeled with anti–RNA-binding protein with multiple splicing (RBPMS; marks 100% of RGCs) and co-labeled with subtype-specific antibodies: CART, melanopsin (OPN4), Foxp2, Islet1/2, SPP1, and Tbr2. RGC loss and subtype distribution were quantified as percentages of RBPMS-positive cells in different retinal regions. Results: In glaucomatous eyes, RGC survival decreased in the retinal periphery, with 65.44% in the dorsal–nasal and 76.03% in the ventral–temporal regions. CART-positive RGCs dropped from 32.9% ± 5.15% to 20.26% ± 2.64% (dorsal–nasal) and from 33.07% ± 4.09% to 22.65% ± 2.65% (ventral–temporal), indicating higher vulnerability. In contrast, OPN4-positive RGCs increased from 3.27% ± 1.34% to 6.99% ± 2.31% (dorsal–nasal), suggesting greater intrinsically photosensitive RGC (ipRGC) resilience. Percentages of SPP1-, Foxp2-, Islet1/2-, and Tbr2-positive RGCs remained unchanged, suggesting proportional loss to total RGC reduction. Conclusions: RGC subtypes showed differing susceptibilities to IOP, with OPN4-positive RGCs (ipRGCs) being more resistant and CART-positive RGCs (ON–OFF direction-selective ganglion cells ooDSGCs) highly vulnerable. This highlights the need to study ooDSGC degeneration and explore targeted neuroprotection. Future research should develop therapies to protect, regenerate, or replace ooDSGCs.
Ruzafa et al. (2025) studied this question.