Dopaminergic Control of Retinal Oscillations Driving Infantile Nystagmus
Infantile nystagmus is a debilitating involuntary eye movement disorder often associated with retinal diseases such as Congenital Stationary Night Blindness (CSNB). The oscillating eye movements of infantile nystagmus come with reduced visual acuity, strongly impairing quality of life. No cure exists for this condition. Previously, we demonstrated that nystagmus in the CSNB mouse model Nyxnob has a retinal cause. Specifically, we found that synchronized oscillations of retinal ganglion cells (RGCs) are transmitted to the accessory optic system, triggering compensatory eye movements. The RGC oscillations appear to originate from a specific retinal cell type, the AII amacrine cell (AII AC), making these cells the preferred target for treatment. Here we found that pharmacologically activating the dopaminergic input to AII ACs in Nyxnob mice completely suppresses the pathological oscillations of both AII ACs and RGCs and improves the signal fidelity of RGCs. Moreover, our retinal network simulations confirm that the experimentally observed changes to AII AC voltage-gated currents are sufficient to account for the dopamine-dependent abolishment of these oscillations. Our findings provide a novel mechanistic understanding of the retinal mechanism underlying infantile nystagmus as well as the associated low visual performance. Consequently, they offer the first pharmacological therapeutic strategy for this disorder. SignificanceOscillatory eye movements in infantile nystagmus arise from abnormal retinal activity, yet the cellular basis of this instability has remained unclear. Here we show that this abnormal activity stems from disrupted dopaminergic modulation. By defining how dopamine regulates the activity of a key retinal cell type, the AII amacrine cell, we demonstrate that restoring dopamine levels can return the retinal circuit to a stable state and improve the clarity of visual signals leaving the eye. This work links neuromodulation to retinal circuit instability and identifies dopaminergic control of AII amacrine cells as a pharmacologically targetable point of intervention. These findings suggest a retina-focused pharmacological treatment strategy for infantile nystagmus, a disorder that currently lacks effective therapeutic options.