Abstract
Purpose :
Glutamate toxicity mediated by NMDA receptors is involved in many retinal diseases, including retinal ischemia and optic nerve injury, which affect many types of retinal ganglion cells (RGCs). Interestingly, a subpopulation of retinal ganglion cells, named intrinsically photosensitive retinal ganglion cells (ipRGCs), are known to be more resistant than other RGCs to retinal injuries. However, the underlying mechanism of their injury-resistant ability is unknown. Distinct from other RGCs, ipRGCs are capable of detecting light without rod and cone photoreceptor cells, owing to their intrinsically expressed light-sensitive GPCR, melanopsin. The relationship between their intrinsic photosensitivity and injury-resistant ability also is not clear. In this work, we used NMDA-induced excitotoxicity model to study the role of melanopsin-mediated phototransduction pathways in the neuroprotective effect of melanopsin.
Methods :
NMDA-mediated neurotoxicity was induced by intravitreally injecting 1 mM NMDA and measured by RGC density change based on immunolabelling with RPBMS, a RGC marker. AAV2-OPN4 virus was intravitreally injected to test the effects of ectopic melanopsin in conventional RGCs. ON- and OFF-α-RGCs were distinguished by immunolabelling with SMI32 antibody on Opn4-Cre;Rosa-tdTomota retina. Trpc6 and Trpc7 double knockout animals were used to examine the involvement of TRP-dependent phototransduction pathway.
Results :
We found that virally expressing melanopsin in conventional RGCs increases their survival rate in NMDA-toxicity model, suggesting that melanopsin is sufficient to provide a neuroprotective effect in RGCs. In addition, M4-ipRGCs, also known as ON-α-RGC, have a higher survival rate than OFF-α-RGCs after NMDA treatment, suggesting that low expression of melanopsin is still capable of providing a neuroprotective effect. Interestingly, knocking out TRPC6 and TRPC7 does not reduce the survival rate of ipRGCs, suggesting that the TRP-dependent transduction pathway is not required for the NMDA-toxicity-resilient ability of ipRGCs.
Conclusions :
Our data indicate that the NMDA-toxicity-resilient ability of ipRGCs does not require TRPC channels and that virally expressed melanopsin is sufficient to provide a neuroprotective effect in conventional RGCs.
This is a 2021 ARVO Annual Meeting abstract.