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

PLoS Biol. 2019 Sep 12;17(9):e3000174. doi: 10.1371/journal.pbio.3000174. eCollection 2019 Sep.

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 night blindness (CSNB) results from primary deficits in the retina. We found that CSNB patients as well as an animal model (nob mice), both of which lacked functional nyctalopin protein (NYX, nyx) in ON bipolar cells (BCs) at their synapse with photoreceptors, showed oscillating eye movements at a frequency of 4-7 Hz. nob ON direction-selective ganglion cells (DSGCs), 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 (GCs) 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 when contrast was present. Retinal pharmacological and genetic manipulations that blocked nob GC oscillations also eliminated their oscillating eye movements, and retinal pharmacological manipulations that reduced the oscillation frequency of nob GCs also reduced the oscillation frequency of their eye movements. We conclude that, in nob mice, synchronized oscillations of retinal GCs, most likely the ON-DCGCs, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Child, Preschool
  • Disease Models, Animal
  • Eye Diseases, Hereditary / physiopathology*
  • Female
  • Genetic Diseases, X-Linked / physiopathology*
  • Humans
  • Infant
  • Male
  • Mice, Knockout
  • Myopia / physiopathology*
  • Night Blindness / physiopathology*
  • Nystagmus, Congenital / etiology*
  • Retinal Ganglion Cells / physiology*

Supplementary concepts

  • Night blindness, congenital stationary

Grant support

This work was supported by a ZonMW grant 91215062 (MK and CIDZ), a grant from Horizon 2020 (number: 674901) “Switchboard” (MK), a grant of ODAS (number: Uitzicht 2011-21) (MK), and a grant from the NIN Friends Foundation. NIH-EY140701 (MAM) and unrestricted funds from the Research to Prevent Blindness (Dept. of Ophthalmology and Visual Sciences, Univ. of Louisville). MAM is a Kentucky Lions Eye Research Endowed Chair. CIDZ is supported by the Dutch Organization for Medical Sciences, Life Sciences, and Social and Behavioral Sciences, NeuroBasic, ERC-adv and ERC-POC, of the EU. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.