ARVO 2023: Early retinal ganglion cell damage in glaucoma

(Image Credit: AdobeStock/New Africa)

Yukihiro Shiga, MD, reported that defective calcium clearance is a characteristic feature of early damage to the retinal ganglion cells (RGC) in a mouse model of glaucoma. Shiga is the lead author of the study from the Neuroscience departments of the Centre Hospitalier de l'Universite de Montreal Centre de Recherche, and the Universite de Montreal, Montreal, Quebec, Canada.

He and his research team conducted this experimental mouse study to determine the mechanisms that cause RGC vulnerability. They hypothesized that RGC calcium dynamics are affected in early-stage ocular hypertension.

In this mouse model, ocular hypertension developed with the intracameral injection of magnetic microbeads. The calcium signals were recorded 2 weeks later before loss of the RGCs. Two-photon laser scanning microscopy recorded the light-evoked RGC calcium dynamics in the living transgenic mice and later in the retinal explants. The calcium signals were extracted. The parameters studied were the calcium influx and clearance times and amplitude, the investigators described.

In this study, the researchers reported that trans-scleral imaging in the live mice and ex vivo imaging showed significant consistent defects in calcium clearance in all RGC types. They found, for example, that optic nerve RGCs that were subjected to ocular hypertension had a significantly (p<0.01) increased calcium decay time compared to sham controls, that is, 2.8 seconds versus 1.1 seconds, respectively.

They explained that when they analyzed the molecular pathways, they observed an “RGC-specific reduction in gene and protein expression of the endoplasmic reticulum (ER) calcium ATPase 2 (SERCS2),” which pumps calcium from the cytoplasm to the ER. This reduced gene and protein expression in the ER was accompanied by up-regulated ER stress markers pPERK, pEIF-2a, ATF4, and CHOP.

The recordings in naïve mice treated with a pharmacologic inhibitor of SERCA2 showed impaired calcium clearance in the RGCs, recapitulating the ocular hypertensive effects.

In contrast, the investigators noted, the glaucomatous eyes treated with a SERCA2-specific activator restored the ability of RGCs to effectively reduce cytoplasmic calcium to physiologic levels.

They concluded, “Our study revealed defective calcium clearance as a signature feature of early RGC damage, a trait conserved across RGC subtypes, and suggested that loss of SERCA2 has a profoundly detrimental effect on the ability of these neurons to regulate cytoplasmic calcium.”