| First Author | Kerov V | Year | 2018 |
| Journal | J Neurosci | Volume | 38 |
| Issue | 27 | Pages | 6145-6160 |
| PubMed ID | 29875267 | Mgi Jnum | J:265366 |
| Mgi Id | MGI:6188383 | Doi | 10.1523/JNEUROSCI.3818-16.2018 |
| Citation | Kerov V, et al. (2018) alpha2delta-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses. J Neurosci 38(27):6145-6160 |
| abstractText | alpha2delta-4 is an auxiliary subunit of voltage-gated Cav1.4 L-type channels that regulate the development and mature exocytotic function of the photoreceptor ribbon synapse. In humans, mutations in the CACNA2D4 gene encoding alpha2delta-4 cause heterogeneous forms of vision impairment in humans, the underlying pathogenic mechanisms of which remain unclear. To investigate the retinal function of alpha2delta-4, we used genome editing to generate an alpha2delta-4 knock-out (alpha2delta-4 KO) mouse. In male and female alpha2delta-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 alpha2delta-4 KO retina. In reconstructions of alpha2delta-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 alpha2delta-4 KO mice correlates with a progressive loss of Cav1.4 channels, first in terminals of rods and later cones. Despite the absence of b-waves in electroretinograms, visually guided behavior is evident in alpha2delta-4 KO mice and better under photopic than scotopic conditions. We conclude that alpha2delta-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.SIGNIFICANCE STATEMENT In the retina, visual information is first communicated by the synapse formed between photoreceptors and second-order neurons. The mechanisms that regulate the structural integrity of this synapse are poorly understood. Here we demonstrate a role for alpha2delta-4, a subunit of voltage-gated Ca(2+) channels, in organizing the structure and function of photoreceptor synapses. We find that presynaptic Ca(2+) channels are progressively lost and that rod and cone synapses are disrupted in mice that lack alpha2delta-4. Our results suggest that alterations in presynaptic Ca(2+) signaling and photoreceptor synapse structure may contribute to vision impairment in humans with mutations in the CACNA2D4 gene encoding alpha2delta-4. |
