Cone dystrophy and ectopic synaptogenesis in a Cacna1f loss of function model of congenital stationary night blindness (CSNB2A).

Abstract

Congenital stationary night blindness 2A (CSNB2A) is an X-linked retinal disorder, characterized by phenotypically variable signs and symptoms of impaired vision. CSNB2A is due to mutations in CACNA1F, which codes for the pore-forming α1F subunit of a L-type voltage-gated calcium channel, Cav1.4. Mouse models of CSNB2A, used for characterizing the effects of various Cacna1f mutations, have revealed greater severity of defects than in human CSNB2A. Specifically, Cacna1f-knockout mice show an apparent lack of visual function, gradual retinal degeneration, and disruption of photoreceptor synaptic terminals. Several reports have also noted cone-specific disruptions, including axonal abnormalities, dystrophy, and cell death. We have explored further the involvement of cones in our 'G305X' mouse model of CSNB2A, which has a premature truncation, loss-of-function mutation in Cacna1f. We show that the expression of genes for several phototransduction-related cone markers is down-regulated, while that of several cellular stress- and damage-related markers is up-regulated; and that cone photoreceptor structure and photopic visual function - measured by immunohistochemistry, optokinetic response and electroretinography - deteriorate progressively with age. We also find that dystrophic cone axons establish synapse-like contacts with rod bipolar cell dendrites, which they normally do not contact in wild-type retinas - ectopically, among rod cell bodies in the outer nuclear layer. These data support a role for Cav1.4 in cone synaptic development, cell viability, and synaptic transmission of cone-dependent visual signals. Although our novel finding of cone-to-rod-bipolar cell contacts in this mouse model of a retinal channelopathy may challenge current views of the role of Cav1.4 in photopic vision, it also suggests a potential new target for restorative therapy.

• Authors: D M Waldner, N C Giraldo Sierra, S Bonfield, L Nguyen, I S Dimopoulos, Y Sauvé, W K Stell, N T Bech-Hansen
• Journal: Channels (Austin, Tex.) (Channels (Austin)) Vol. 12 Issue 1 Pg. 17-33 (01 01 2018) ISSN: 1933-6969 [Electronic] United States
• PMID: 29179637 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cacna1f protein, mouse
• Calcium Channels
• Calcium Channels, L-Type

Topics

• Animals
• Calcium Channels (deficiency, genetics, metabolism)
• Calcium Channels, L-Type
• Cone Dystrophy (metabolism)
• Disease Models, Animal
• Eye Diseases, Hereditary (metabolism, pathology)
• Female
• Genetic Diseases, X-Linked (metabolism, pathology)
• Mice
• Mice, Knockout
• Mutation
• Myopia (metabolism, pathology)
• Night Blindness (metabolism, pathology)
• Synapses (metabolism)