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Abstract
There is increasing evidence for the vulnerability of specific retinal ganglion cell (RGC) types in those with glaucoma and in animal models. In addition, the P2X7-receptor (P2X7-R) has been suggested to contribute to RGC death following stimulation and elevated IOP, though its role in RGC dysfunction prior to death has not been examined. Therefore, we examined the effect of an acute, non-ischemic intraocular pressure (IOP) insult (50 mmHg for 30 min) on RGC function in wildtype mice and P2X7-R knockout (P2X7-KO) mice. We examined retinal function using electroretinogram recordings and individual RGC responses using multielectrode arrays, 3 days following acute IOP elevation. Immunohistochemistry was used to examine RGC cell death and P2X7-R expression in several RGC types. Acute intraocular pressure elevation produced pronounced dysfunction in RGCs; whilst other retinal neuronal responses showed lesser changes. Dysfunction at 3 days post-injury was not associated with RGC loss or changes in receptive field size. However, in wildtype animals, OFF-RGCs showed reduced spontaneous and light-elicited activity. In the P2X7-KO, both ON- and OFF-RGC light-elicited responses were reduced. Expression of P2X7-R in wildtype ON-RGC dendrites was higher than in other RGC types. In conclusion, OFF-RGCs were vulnerable to acute IOP elevation and their dysfunction was not rescued by genetic ablation of P2X7-R. Indeed, knockout of P2X7-R also caused ON-RGC dysfunction. These findings aid our understanding of how pressure affects RGC function and suggest treatments targeting the P2X7-R need to be carefully considered.
Highlights
There is increasing evidence for the vulnerability of specific retinal ganglion cell (RGC) types in those with glaucoma and in animal models
This study demonstrates that an acute increase in intraocular pressure (IOP) is sufficient to cause RGC dysfunction
In WT mice, OFF-RGCs showed a reduction in activity 3 days after acute IOP stress, which occurred in the absence of cell loss
Summary
There is increasing evidence for the vulnerability of specific retinal ganglion cell (RGC) types in those with glaucoma and in animal models. RGCs are the output neurons of the retina, transmitting signals along their axons to the brain They are a heterogenous population that can be divided broadly into ON-, OFF- and ON–OFF functional groups based on a response to light increment, decrement, or b oth[4,5,6]. Given these functional differences and their structural and molecular underpinnings, understanding how different RGC types are affected by pressure may give greater insights into the degeneration process during glaucoma[7]. Excessive stimulation of P2X7-R with a gonists18–21, ischemia[21] or severe pressure (90 mmHg21)
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