Sildenafil-driven cone PDE6 inhibition alters receptive-field properties of retinal ganglion cells ex vivo

Suppressing the phototransduction cascade has a profound impact on visual information processing in the retina. Here, we examined how acute silencing of photoreceptors alters stimulus preference of Retinal Ganglion Cells (RGCs) without affecting retinal anatomy. Using ex vivo recordings from C57BL/6 mouse retinas, we applied the phosphodiesterase 6 (PDE6) inhibitor Sildenafil and compared responses to flash and drifting-grating stimuli before and after treatment. Flash responses revealed six physiological RGC populations under control conditions. After Sildenafil, Off-responses were completely abolished, and most cells adopted On-like profiles with markedly prolonged response latencies. At the population level, orientation selectivity was preserved; however, RGCs lost the ability to detect spatial frequencies above 0.05 cycle/{degrees} and temporal frequencies above 2 cycle/s. A subset of cells increased their firing rates and transformed from orientation-selective into direction-selective cells, indicating reorganization of tuning properties. To assess photoreceptor specificity of Sildenafil, we tested Gnat1 (rod-deficient, cone-only) and Gnat2 (cone-deficient, rod-only) mouse models. Sildenafil completely removed visually evoked responses in Gnat1 retinas, but not in Gnat2, demonstrating preferential inhibition of cone PDE6. These results show that cone-selective suppression of phototransduction is sufficient to abolish Off-pathway signaling, reduce high-frequency visual sensitivity, and alter RGC receptive-field tuning. Beyond providing a mechanistic explanation for the visual side effects of PDE5/6 inhibitors, this establishes a pharmacological model to mimic early cone dysfunction and study inner retinal adaptation. Significance StatementPhotoreceptor degeneration alters visual processing long before anatomical changes are evident, but the early functional consequences for retinal circuits remain poorly defined. Here, we show that pharmacological suppression of phototransduction with the PDE6 inhibitor Sildenafil selectively abolishes cone-driven responses and profoundly alters retinal ganglion cell tuning. Off-pathway signaling is lost, spatiotemporal frequency sensitivity is reduced, and some cells acquire direction selectivity. These findings provide functional evidence that cone pathways are preferentially targeted by Sildenafil, offering a mechanistic explanation for its transient visual side effects in humans. More broadly, this approach establishes a pharmacological model for studying inner retinal adaptation to early cone dysfunction in degenerative disease.