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InNyxnobmice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), synchronous oscillating retinal ganglion cells (RGCs) lead to oscillatory eye movements, i.e., nystagmus. Given the distribution ofmGluR6andCav1.4in the retina as well as their clinical association with CSNB, we hypothesize thatmGluR6-/-andCav1.4-/-mutants show, like theNyxnobmouse, oscillations that originate in the AIIamacrine cells (AIIACs). Using eye movement and multi-electrode array (MEA) recordings of RGCs we show that the nystagmus as well as the underlying RGC oscillations are also present inmGluR6-/-andCav1.4-/-mice. Yet, we find that the oscillations in themGluR6-/-andCav1.4-/-mutants slightly differ from each other and also from those of theNyxnobmice. Moreover, each of the three mutations likely impacts the membrane potential of the AIIACs differently. Together our results indicate that nystagmus and oscillating RGCs are generalizable features associated with CSNB mutations localized at the photoreceptor-bipolar cell synapse.

Congenital nystagmus, involuntary oscillating small eye movements, is commonly thought to originate from aberrant interactions between brainstem nuclei and foveal cortical pathways. Here we investigated whether nystagmus associated with congenital stationary nightblindness (CSNB) can result from primary deficits in the retina. We found that CSNB patients as well as an animal model (nob mice), both of which lack functional nyctalopin protein (NYX, nyx) in ON bipolar cells (ON-BC) at their synapse with photoreceptors, showed oscillating eye movements at a frequency of 4-7Hz. nob ON direction selective ganglion cells (ON-DSGC), which detect global motion and project to the accessory optic system (AOS), oscillated with the same frequency as their eyes. In the dark, individual ganglion cells (GC) oscillated asynchronously, but their oscillations became synchronized by light stimulation. Likewise, both patient and nob mice oscillating eye movements were only present in the light. Retinal pharmacological manipulations that blocked nob ON-DSGC oscillations also eliminated their oscillating eye movements, and retinal pharmacological manipulations that reduced oscillation frequency of nob ON-DSGCs also reduced oscillation frequency of their eye movements. We conclude that, in nob mice, oscillations of retinal ON-DSGCs cause nystagmus with properties similar to those associated with CSNB in humans. These results show that the nob mouse is the first animal model for a form of congenital nystagmus paving the way for development of therapeutic strategies.