GPR88 in ON Direction-Selective Ganglion Cells Suppresses Myopia Development

Purpose: Myopia (near-sightedness) is a major public health issue worldwide, especially in Asia. Retinal ganglion cells (RGCs), the main output neurons of the retina, are essential for visual signal transmission and ocular development. Direction-selective RGCs, such as ON direction-selective RGCs (ON dsRGCs), contribute to motion vision and image stabilization. Studies indicate that ON pathway mutations may increase myopia development. ON dsRGCs with Gpr88 expression show resistance to injury, suggesting a survival advantage in many diseases. We hypothesize that Gpr88-expressing ON dsRGCs, via an intact ON pathway, help restrain myopia development. This study evaluates whether Gpr88 signaling in ON dsRGCs is involved in ON pathway function and could represent a novel target for myopia control.
Methods: Lens-induced myopia models were established in transgenic mice to assess axial length and refractive error changes. In Gpr88-/- crossed with iDTR mice (Gpr88*iDTR), the ON dsRGC was selectively ablated, and myopia development was compared to wild-type(WT) controls. The Gpr88 -/- mice were also evaluated for myopia development relative to WT mice. Visual motion function was assessed using optokinetic response (OKR). Patch clamp recordings were performed on ON dsRGCs from Gpr88-/- and WT mice. Single-cell RNA sequencing examined Gpr88 expression level changes in the myopic retina group. All mice were maintained on a 12-hour light/dark cycle. Statistical analyses used t-tests and ANOVA.
Results: Ablation of the ON dsRGC pathway in Gpr88*iDTR mice led to significantly increased myopia development compared to controls (n=6, p<0.05). OKR sensitivity was significantly reduced in Gpr88*iDTR mice (n=4, p<0.01). Consistent with the notion that Gpr88 is expressed in ON-DSGCs. Single-cell RNA sequencing revealed significant downregulation of Gpr88 expression in retinas with high myopia (p<0.05).
Conclusions: Gpr88 gene is expressed in RGC subtypes, particularly ON dsRGCs, and loss of Gpr88/ON dsRGC function exacerbates myopia and impairs motion-driven visual responses, consistent with disruption of the ON pathway. These findings suggest that Gpr88 supports normal ocular growth regulation and may be a promising target for gene-based myopia suppression.