Photoreceptor contributions to refractive eye growth and myopia

Purpose: The specific retinal pathways that detect visual input and initiate the signaling for refractive eye growth are unknown. We evaluated the potential influence of the three photoreceptor pathways: rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs) by evaluating refractive development in mice with mutations in these pathways. Methods: Refractive development was measured bi-weekly from postnatal day (P) 28 to P112 in mice with non-functional rods (Gnat1-/-), cones (Gnat2-/-), or ipRGCs (Opn4-/-), compared to wild-type (WT) age-matched controls. Refraction was measured using an automated photorefractor, corneal curvature with keratometry, and ocular parameters (axial length, lens thickness, etc), with spectral-domain optical coherence tomography. Separate cohorts of mice wore a unilateral diffuser goggle to induce monocular form-deprivation (FD) myopia starting at P28 and were tested weekly. Results: Refractive development in Gnat1-/- mice was abnormal with no substantial change in refractive error from P28-P84 while WT counterparts showed a shift towards hyperopia that plateaued about P42. Additionally, 3 weeks of FD had no effect on Gnat1-/- mice, while WT mice showed significant myopic shifts. In contrast, Gnat2-/- mice showed a similar refractive development curve to WT controls under normal laboratory conditions. Three weeks of FD produced significantly greater myopic shifts in Gnat2-/- mice compared to WT controls (p<0.04). With unimpaired visual input, Opn4-/- mice had abnormal refractive development with more myopic refractions than their WT counterparts at P28 that then shifted after P56 towards more hyperopic refractions than WT controls by P112. After 3 weeks of FD, goggled Opn4-/- mice showed a significantly greater myopic shift than WT controls (p<0.001). Conclusions: Our findings suggest that photoreceptor pathways differentially influence refractive development. Disruption of rod or ipRGC pathways appeared to significantly alter refractive development under normal and FD conditions, although in different directions. Surprisingly, disrupted cone pathways which are needed for high acuity vision in primates did not affect refractive development under normal conditions and had minimal effects on the response to FD. We will discuss the potential role of dopamine as a stop signal for refractive eye growth and its regulation by these pathways.