Nystagmus in patients with congenital stationary night blindness (CSNB) originates from synchronously firing direction-selective retinal ganglion cells

Abstract

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 25 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 30 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 35 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.

A Common Cause for Nystagmus in Different Congenital Stationary Night Blindness Mouse Models

“…Multielectrode RGC recordings were performed as described previously (Winkelman et al, 2019;Hölzel et al, 2022). After at least one hour of dark adaptation, mice were sedated using a mixture of CO2/O2 and ultimately euthanized by cervical dislocation.…”

“…Full field white light flashes were generated using Psychophysics Toolbox Version 3 (Brainard, 1997) and presented to the photoreceptor side of the retina with a custom-modified DLP projector (for details of modification see Winkelman et al, 2019;Light Crafter 4500, Wintech, Carlsbad, CA, USA). For WT, Nyx nob and Cav1.4 -/retinas, the full field light flash had a duration of 500 ms.…”

“…On the other hand, the OKRs of mGluR6 -/-, Nyx nob and Cav1.4 -/mice were severely impaired and had had different characteristics in each mutant. mGluR6 -/and Nyx nob mice initially follow the gratings moving in the temporal to nasal direction (arrows), but were unable to maintain this eye movement (also see Winkelman et al, 2019). Furthermore, their eyes tended to drift when the grating stopped moving.…”

“…These involuntary, oscillating eye movements occur shortly after birth and vary from pendular to jerk nystagmus (Optican & Zee, 1984;Pieh et al, 2008). Previously, we reported that Nyx nob mice, a CSNB mouse model (Pardue et al, 1998;Gregg et al, 2003), have a pendular nystagmus that results from the oscillatory output of retinal ganglion cells (RGCs, Winkelman et al, 2019). This oscillatory firing of RGC is driven by AII amacrine cells (AII ACs), which are most likely depolarized outside of their normal working range due to the lack of ON-bipolar cell (ON-BC) input (Winkelman et al, 2019).…”

“…Previously, we reported that Nyx nob mice, a CSNB mouse model (Pardue et al, 1998;Gregg et al, 2003), have a pendular nystagmus that results from the oscillatory output of retinal ganglion cells (RGCs, Winkelman et al, 2019). This oscillatory firing of RGC is driven by AII amacrine cells (AII ACs), which are most likely depolarized outside of their normal working range due to the lack of ON-bipolar cell (ON-BC) input (Winkelman et al, 2019). The photoreceptor to ON-BC synapse is a highly specialized metabotropic glutamatergic synapse (Fig 1).…”