Abstract
Purpose :
The voltage-gated calcium channel, Cav1.4 is localized to photoreceptor ribbon synapses and functions both in molecular organization of the synapse and in regulating release of synaptic vesicles. Cav1.4 is composed of three subunits – the pore-forming α1F, an intracellular β2a, and an extracellular α2δ4. Mutations in Cav1.4 subunits typically present as either congenital stationary night blindness, type 2 or a progressive cone-rod dystrophy in humans. Several knockout mice for the various Cav1.4 subunits have been studied. Since cones only represent 3% of photoreceptors, we need a cone-rich mammalian model system to study why different Cav1.4 mutations affect rods and cones differently.
Methods :
NRL-/-; RPE65 R91W+ “Conefull” mice were crossed to Cav1.4 α1F or α2δ4 KO mice to generate the ‘Conefull:α1F KO’ and ‘Conefull:α2δ4 KO’ lines. Retina structure and function was assessed using a visually guided water maze, electroretinogram (ERG), optical coherence tomography (OCT) and histology. Mice of both sexes and up to six-months of age were used.
Results :
Conefull: α1F KO mice could not navigate the visually guided water maze, had a no b-wave ERG phenotype, and the developing all-cone outer nuclear layer reorganized into rosettes at the time of eye opening with degeneration progressing to 30% loss by 2-months of age. In comparison, the Conefull: α2δ4 KO mice successful navigated the visually guided water maze, had a reduced amplitude b-wave ERG, and the development of the all-cone outer nuclear layer appeared normal although progressive degeneration with 10% loss by 2-months of age was observed
Conclusions :
New disease models for studying congenital synaptic diseases due to loss of Cav1.4 function have been created for focused analysis of mammalian cones. Like what has been described in normal rod-dominant mouse retinas, loss of the α1F subunit is more disruptive than loss of the α2δ4 subunit. A major difference is that in the all-cone retina loss of the α1F subunit triggers gross reorganization and degeneration of cones earlier than expected.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.