Differential vulnerability of Brn3b expressing retinal ganglion subtypes in inherited and induced mouse model of retinal degeneration

The retinal ganglion cells (RGCs) are the output neurons of the retina that transmit light signals to the brain for processing and are classified into different subtypes. The melanopsin containing RGCs (ipRGCs) are increasingly preferred for optogenetic therapeutic intervention to treat inherited retinal degeneration (RD) due to their proposed role in image recognition. Here, we investigated the effects of RD on Brn3b and SMI32 expressing ipRGCs using rd1 mice and N-methyl-N-nitrosourea (MNU) injected mice that mimics retinitis pigmentosa. We examined the overall retinal thickness in response to photoreceptor degeneration. Retinal sections were subjected to immunostaining of Brn3b, a transcription factor important for RGC development and SMI32, a neurofilament marker that labels alpha RGCs. We demonstrate significant decrease of retinal thickness after complete loss of photoreceptors. However, the overall population of the ipRGCs across the experimental groups remained unchanged. Interestingly, MNU treated mice showed a marked reduction in Brn3b expressing cells while the expression of SMI32 remained unaltered. On the contrary, rd1 mice did not exhibit significant changes in the expression of either of the markers, Brn3b or SMI32. Our results suggest that overall distribution of ipRGCs remained unaffected in both models of degeneration, rd1 and MNU-treated mice. Although MNU-treated mice showed reduced levels of Brn3b, compared to rd1 and WT, the levels of SMI32 remained unaffected across the experimental groups. Since Brn3b fine-tunes melanopsin expression, reduction of Brn3b might result in feedback regulation to elevate expression of melanopsin in ipRGCs as their total number remained unaltered in RD.