LRIT3 Differentially Affects Connectivity and Synaptic Transmission of Cones to ON- and OFF-Bipolar Cells

Invest Ophthalmol Vis Sci. 2017 Mar 1;58(3):1768-1778. doi: 10.1167/iovs.16-20745.


Purpose: Mutations in LRIT3 lead to complete congenital stationary night blindness (cCSNB). Using a cCSNB mouse model lacking Lrit3 (nob6), we recently have shown that LRIT3 has a role in the correct localization of TRPM1 (transient receptor potential melastatin 1) to the dendritic tips of ON-bipolar cells (BCs), contacting both rod and cone photoreceptors. Furthermore, postsynaptic clustering of other mGluR6 cascade components is selectively eliminated at the dendritic tips of cone ON-BCs. The purpose of this study was to further define the role of LRIT3 in structural and functional organization of cone synapses.

Methods: Exhaustive electroretinogram analysis was performed in a patient with LRIT3 mutations. Multielectrode array recordings were performed at the level of retinal ganglion cells in nob6 mice. Targeting of GluR1 and GluR5 at the dendritic tips of OFF-BCs in nob6 retinas was assessed by immunostaining and confocal microscopy. The ultrastructure of photoreceptor synapses was evaluated by electron microscopy in nob6 mice.

Results: The patient with LRIT3 mutations had a selective ON-BC dysfunction with relatively preserved OFF-BC responses. In nob6 mice, complete lack of ON-pathway function with robust, yet altered signaling processing in OFF-pathways was detected. Consistent with these observations, molecules essential for the OFF-BC signaling were normally targeted to the synapse. Finally, synaptic contacts made by ON-BC but not OFF-BC neurons with the cone pedicles were disorganized without ultrastructural alterations in cone terminals, horizontal cell processes, or synaptic ribbons.

Conclusions: These results suggest that LRIT3 is likely involved in coordination of the transsynaptic communication between cones and ON-BCs during synapse formation and function.

Publication types

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

MeSH terms

  • Animals
  • DNA / genetics*
  • DNA Mutational Analysis
  • Dendrites / metabolism
  • Dendrites / ultrastructure
  • Electroretinography
  • Eye Diseases, Hereditary / genetics*
  • Eye Diseases, Hereditary / metabolism
  • Eye Diseases, Hereditary / pathology
  • Female
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / metabolism
  • Genetic Diseases, X-Linked / pathology
  • Humans
  • Immunohistochemistry
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Mutation*
  • Myopia / genetics*
  • Myopia / metabolism
  • Myopia / pathology
  • Night Blindness / genetics*
  • Night Blindness / metabolism
  • Night Blindness / pathology
  • Retinal Bipolar Cells / metabolism*
  • Retinal Bipolar Cells / ultrastructure
  • Retinal Cone Photoreceptor Cells / metabolism*
  • Retinal Cone Photoreceptor Cells / ultrastructure
  • Retrospective Studies
  • Synapses / metabolism
  • Synapses / ultrastructure*
  • Synaptic Transmission / genetics
  • Young Adult


  • Lrit3 protein, mouse
  • Membrane Proteins
  • DNA

Supplementary concepts

  • Night blindness, congenital stationary