Abstract
TRPM1 channels, regulated by mGluR6 at the dendrites of retinal ON bipolar cells (BCs), play a crucial role in visual signal transduction. Both Trpm1 knockout (KO) and mGluR6 KO mice are models of congenital stationary night blindness with grossly normal morphology. However, robust pathological spontaneous oscillations in retinal ganglion cells (RGCs) have been observed in Trpm1 KO retinas but not in mGluR6 KO retinas. We investigated the mechanism underlying these oscillations in the Trpm1 KO retina using whole-cell clamp techniques. We found that inhibitory and excitatory synaptic inputs produced anti-phase oscillations in OFF and ON RGCs, respectively, and that oscillations could be suppressed by blockers targeting the AII amacrine cell (AC) pathway. The rd1 retina, a model for retinitis pigmentosa with severe photoreceptor degeneration, displays similar oscillations to the Trpm1 KO retina. Morphological and immunohistochemical analyses revealed similar alterations in the Trpm1 KO and rd1 retinas when compared to the mGluR6 KO and wild-type retinas: namely, rod BCs (RBCs) in both Trpm1 KO and rd1 retinas showed reduced dendritic TRPM1 labeling and smaller axon terminals. Furthermore, RBCs in the Trpm1 KO retina were significantly hyperpolarized. In silico simulation of the BC-AII AC-RGC network suggests that the reduction of RBC and ON cone BC outputs to AII ACs contributes to RGC oscillations. Our findings suggest that TRPM1 deficiency in ON BCs produces RGC oscillations in association with RBC axon remodeling and reduced ON BC outputs, and may represent a shared circuit mechanism underlying pathological oscillations across different causes of outer retinal diseases.