Subtype specific retinal ganglion cell dysfunction in a mouse model of ocular hypertension

Purpose:Glaucoma is a neurodegenerative disorder characterized by retinal ganglion cell (RGC) loss. Previous studies suggest that there may be specific types of RGCs that are more vulnerable to elevated intraocular pressure (IOP). The purpose of this study is to determine the effects of laser-induced ocular hypertension (LIOH) on various subtypes of RGCs at different time points after IOP elevation. Methods:IOP was elevated unilaterally using laser photocoagulation of the limbal and episcleral vessels in adult CD-1 mouse eyes. Three, 7, 14, and 30 days after IOP elevation, multielectrode array recordings were performed to simultaneously record from RGCs in the intact retina. Based on their response to a square-wave light stimulus, the RGCs were classified into four subtypes: OFF transient, OFF sustained, ON transient, and ON sustained. Various light response properties including receptive field (RF) size, spike threshold, gain, and maximal spike rate were quantified. In addition, whole-mount retina immunohistochemistry was performed using SMI-32 to label RGCs. Results:Spontaneous activity was decreased in three of the four RGC types 30 days after IOP elevation. However, OFF transient RGCs showed the earliest decrease in spontaneous activity at 14 days. The ON sustained and OFF sustained RGCs also showed decline in spontaneous activity, but not until 30 days. Lastly, the ON transient RGCs did not have any alteration in spontaneous activity across all time points. We further investigated the light responses of these RGC subtypes by using Gaussian white noise stimulation and reverse-correlation methods to evaluate the spatial structure of the receptive field (RF) of neighboring cells. A significant decrease in RF size was found only in the OFF transient RGCs, as early as 7 days after IOP elevation. None of the other RGC subtypes demonstrated changes in average RF size. Examination of the ON and OFF alpha-like RGCs by SMI-32 immunostaining revealed that the proportion of OFF transient RGCs lost was greater than ON sustained RGCs at 14 days. Conclusions:Taken together, these data suggest that IOP elevation differentially affects various RGC subtypes. OFF transient RGCs exhibit the earliest decline in function whereas ON transient RGCs exhibit relative resistance to elevated IOP, which is consistent across distinct approaches to elevate IOP including the microbead occlusion model.