PURPOSE. Ca v 1.4 is a voltage-gated calcium channel clustered at the presynaptic active zones of photoreceptors. Ca v 1.4 functions in communication by mediating the Ca 2þ influx that triggers neurotransmitter release. It also aids in development since rod ribbon synapses do not form in Ca v 1.4 knockout mice. Here we used a rescue strategy to investigate the ability of Ca v 1.4 to trigger synaptogenesis in both immature and mature mouse rods. METHODS. In vivo electroporation was used to transiently express Ca v a 1F or tamoxifeninducible Ca v a 1F in a subset of Ca v 1.4 knockout mouse rods. Synaptogenesis was assayed using morphologic markers and a vision-guided water maze. RESULTS. We found that introduction of Ca v a 1F to knockout terminals rescued synaptic development as indicated by PSD-95 expression and elongated ribbons. When expression of Ca v a 1F was induced in mature animals, we again found restoration of PSD-95 and elongated ribbons. However, the induced expression of Ca v a 1F led to diffuse distribution of Ca v a 1F in the terminal instead of being clustered beneath the ribbon. Approximately a quarter of treated animals passed the water maze test, suggesting the rescue of retinal signaling in these mice. CONCLUSIONS. These data confirm that Ca v a 1F expression is necessary for rod synaptic terminal development and demonstrate that rescue is robust even in adult animals with late stages of synaptic disease. The degree of rod synaptic plasticity seen here should be sufficient to support future vision-restoring treatments such as gene or cell replacement that will require photoreceptor synaptic rewiring.

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. Mutations in Cav1.4 subunits typically present as either incomplete congenital stationary night blindness or a progressive cone-rod dystrophy in humans. We developed a cone-rich mammalian model system to further study how different Cav1.4 mutations affect cones. RPE65 R91W KI; Nrl KO “Conefull” mice were crossed to Cav1.4 α1F or α2δ4 KO mice to generate the “Conefull:α1F KO” and “Conefull:α2δ4 KO” lines. Animals were 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. Conefull: α1F KO mice could not navigate the visually guided water maze, had no b-wave in the ERG, 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 successfully 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. In summary, new disease models for studying congenital synaptic diseases due to loss of Cav1.4 function have been created.