Abstract
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.