Dysregulation of Ca(v)1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2

Channels (Austin). 2013 Nov-Dec;7(6):514-23. doi: 10.4161/chan.26376. Epub 2013 Sep 24.


Mutations in the gene encoding Cav 1.4, CACNA1F, are associated with visual disorders including X-linked incomplete congenital stationary night blindness type 2 (CSNB2). In mice lacking Cav 1.4 channels, there are defects in the development of "ribbon" synapses formed between photoreceptors (PRs) and second-order neurons. However, many CSNB2 mutations disrupt the function rather than expression of Cav 1.4 channels. Whether defects in PR synapse development due to altered Cav 1.4 function are common features contributing to the pathogenesis of CSNB2 is unknown. To resolve this issue, we profiled changes in the subcellular distribution of Cav 1.4 channels and synapse morphology during development in wild-type (WT) mice and mouse models of CSNB2. Using Cav 1.4-selective antibodies, we found that Cav 1.4 channels associate with ribbon precursors early in development and are concentrated at both rod and cone PR synapses in the mature retina. In mouse models of CSNB2 in which the voltage-dependence of Cav 1.4 activation is either enhanced (Cav 1.4I756T) or inhibited (CaBP4 KO), the initial stages of PR synaptic ribbon formation are largely unaffected. However, after postnatal day 13, many PR ribbons retain the immature morphology. This synaptic abnormality corresponds in severity to the defect in synaptic transmission in the adult mutant mice, suggesting that lack of sufficient mature synapses contributes to vision impairment in Cav 1.4I756T and CaBP4 KO mice. Our results demonstrate the importance of proper Cav 1.4 function for efficient PR synapse maturation, and that dysregulation of Cav 1.4 channels in CSNB2 may have synaptopathic consequences.

Keywords: CACNA1F; Ca2+ channel; Cav1.4; congenital stationary night blindness; photoreceptor; retina; ribbon synapse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium Channels / deficiency
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Channels, L-Type
  • Eye Diseases, Hereditary / genetics
  • Eye Diseases, Hereditary / metabolism*
  • Eye Diseases, Hereditary / pathology*
  • Female
  • Gene Knockout Techniques
  • Genetic Diseases, X-Linked / genetics
  • Genetic Diseases, X-Linked / metabolism*
  • Genetic Diseases, X-Linked / pathology*
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Molecular Sequence Data
  • Myopia / genetics
  • Myopia / metabolism*
  • Myopia / pathology*
  • Night Blindness / genetics
  • Night Blindness / metabolism*
  • Night Blindness / pathology*
  • Protein Transport
  • Retinal Cone Photoreceptor Cells / pathology*
  • Retinal Rod Photoreceptor Cells / pathology*
  • Synapses / metabolism*


  • Cacna1f protein, mouse
  • Calcium Channels
  • Calcium Channels, L-Type

Supplementary concepts

  • Night blindness, congenital stationary