Classical Photoreceptors Are Primarily Responsible for the Pupillary Light Reflex in Mouse

Pupillary light reflex (PLR) is an important clinical tool to assess the integrity of visual pathways. The available evidence suggests that melanopsin-expressing retinal ganglion cells (mRGCs) mediate PLR-driven by the classical photoreceptors (rods and cones) at low irradiances and by melanopsin activation at high irradiances. However, genetic or pharmacological elimination of melanopsin does not completely abolish PLR at high irradiances, raising the possibility that classical photoreceptors may have a role even at high irradiances. Using an inducible mouse model of photoreceptor degeneration, we asked whether classical photoreceptors are responsible for PLR at all irradiances, and found that the PLR was severely attenuated at all irradiances. Using multiple approaches, we show that the residual PLR at high irradiances in this mouse was primarily from the remnant rods and cones, with a minor contribution from melanopsin activation. In contrast, in rd1 mouse where classical photoreceptor degeneration occurs during development, the PLR was absent at low irradiances but intact at high irradiances, as reported previously. Since mRGCs receive inputs from classical photoreceptors, we also asked whether developmental loss of classical photoreceptors as in rd1 mouse leads to compensatory takeover of the high-irradiance PLR by mRGCs. Specifically, we looked at a distinct subpopulation of mRGCs that express Brn3b transcription factor, which has been shown to mediate PLR. We found that rd1 mouse had a significantly higher proportion of Brn3b-expressing M1 type of mRGCs than in the inducible model. Interestingly, inducing classical photoreceptor degeneration during development also resulted in a higher proportion of Brn3b-expressing M1 cells and partially rescued PLR at high irradiances. These results suggest that classical photoreceptors are primarily responsible for PLR at all irradiances, while melanopsin activation makes a minor contribution at very high irradiances.