β₂δ-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses

β₂δ-4 is an auxiliary subunit of voltage-gated Ca_v1.4 L-type channels that regulate the development and mature exocytotic function of the photoreceptor ribbon synapse. In humans, mutations in the CACNA2D4 gene encoding β₂δ-4 cause heterogeneous forms of vision impairment in humans, the underlying pathogenic mechanisms of which remain unclear. To investigate the retinal function of β₂δ-4, we used genome editing to generate an β₂δ-4 knock-out (β₂δ-4 KO) mouse. In male and female β₂δ-4 KO mice, rod spherules lack ribbons and other synaptic hallmarks early in development. Although the molecular organization of cone synapses is less affected than rod synapses, horizontal and cone bipolar processes extend abnormally in the outer nuclear layer in β₂δ-4 KO retina. In reconstructions of β₂δ-4 KO cone pedicles by serial block face scanning electron microscopy, ribbons appear normal, except that less than one-third show the expected triadic organization of processes at ribbon sites. The severity of the synaptic defects in β₂δ-4 KO mice correlates with a progressive loss of Ca_v1.4 channels, first in terminals of rods and later cones. Despite the absence of b-waves in electroretinograms, visually guided behavior is evident in β₂δ-4 KO mice and better under photopic than scotopic conditions. We conclude that β₂δ-4 plays an essential role in maintaining the structural and functional integrity of rod and cone synapses, the disruption of which may contribute to visual impairment in humans with CACNA2D4 mutations.