alpha(2)delta-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses

作者：Kerov Vasily; Laird Joseph G; Joiner Mei ling; Knecht Sharmon; Soh Daniel; Hagen Jussara; Gardner Sarah H; Gutierrez Wade; Yoshimatsu Takeshi; Bhattarai Sajag; Puthussery Teresa; Artemyev Nikolai O; Drack Arlene V; Wong Rachel O; Baker Sheila A^*; Lee Amy^*

来源：Journal of Neuroscience, 2018, 38(27): 6145-6160.

DOI：10.1523/JNEUROSCI.3818-16.2018

• Ca2+ channel
• photoreceptor
• retina
• ribbon synapse
• synaptogenesis

alpha(2)delta-4 is an auxiliary subunit of voltage-gated Ca(v)1.4 L-type channels that regulate the development and mature exocytotic function of the photoreceptor ribbon synapse. In humans, mutations in the CACNA2D4 gene encoding alpha(2)delta-4 cause heterogeneous forms of vision impairment in humans, the underlying pathogenic mechanisms of which remain unclear. To investigate the retinal function of alpha(2)delta-4, we used genome editing to generate an alpha(2)delta-4 knock-out (alpha(2)delta-4 KO) mouse. In male and female alpha(2)delta-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 alpha(2)delta-4 KO retina. In reconstructions of alpha(2)delta-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 alpha(2)delta-4 KO mice correlates with a progressive loss of Ca(v)1.4 channels, first in terminals of rods and later cones. Despite the absence of b-waves in electroretinograms, visually guided behavior is evident in alpha(2)delta-4 KO mice and better under photopic than scotopic conditions. We conclude that alpha(2)delta-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.

• 出版日期2018-7-4