Abstract
Purpose :
Glaucoma typically features elevated intraocular pressure (IOP) and progressive degeneration of retinal ganglion cells (RGCs) whose axons comprise the optic nerve. While overall RGC demise leads to permanent vision loss, we do not know whether type-specific RGC degeneration preceding cell death contributes to visual decline reported by patients. To address this, we performed patch clamp recordings from a defined subset of RGCs to examine their light-evoked synaptic inputs and spike outputs in healthy versus glaucomatous retinas.
Methods :
We used backcrossing and speed congenics to develop parvalbuminCre-YFP reporter mice congenic to the DBA/2J background. In these mice, 8 RGC types express YFP and mice develop progressively increased IOP (glaucoma). We targeted YFP+ OFF-transient alpha RGCs (OFF-t-αRGCs) in these mice and performed patch clamp recordings to examine light-evoked excitatory postsynaptic currents (L-EPSCs) and light-evoked spiking. We grouped our data into (0-3 mo) or old (>12mo) DBA2J/PV-YFP retinas. RGCs were stimulated with light spots of varying sizes or contrasts. Recorded cells were filled with Neurobiotin and morphology quantified by Scholl analysis, dendritic area/length, and number of branch points.
Results :
Regardless of spot size or contrast, OFF-t-αRGCs in old, glaucomatous retinas exhibited L-EPSCs that were comparable to young mice. In contrast, these RGCs had a ~60% reduction in spike output to all spot sizes/contrasts. They also lost surround inhibition (full-field stimuli). Glaucomatous OFF-t-αRGCs were more likely to be unresponsive to small spots or weak contrast stimuli. When we quantified OFF-t-αRGC dendritic morphology we found no difference between healthy and diseased age-matched retinas.
Conclusions :
Our findings demonstrate that afferent excitatory synaptic input to OFF-t-αRGCs is unaffected by glaucoma pathogenesis. However, these RGCs exhibit deficits in efferent spike output. Furthermore, OFF-t-αRGCs in diseased retinas appear to be morphologically normal. Collectively, our results predict that glaucomatous OFF-t-αRGCs suffer a loss of intrinsic excitability that could lead to difficulty perceiving dark contrasts in the visual field, especially for stimuli of low contrast or fine spatial acuity. Ongoing studies will evaluate the loss of excitability in glaucomatous OFF-t-αRGCs and their consequences in dLGN input.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.