The Auxiliary Calcium Channel Subunit α2δ4 Is Required for Axonal Elaboration, Synaptic Transmission, and Wiring of Rod Photoreceptors

Neuron. 2017 Mar 22;93(6):1359-1374.e6. doi: 10.1016/j.neuron.2017.02.021. Epub 2017 Mar 2.


Neural circuit wiring relies on selective synapse formation whereby a presynaptic release apparatus is matched with its cognate postsynaptic machinery. At metabotropic synapses, the molecular mechanisms underlying this process are poorly understood. In the mammalian retina, rod photoreceptors form selective contacts with rod ON-bipolar cells by aligning the presynaptic voltage-gated Ca2+ channel directing glutamate release (CaV1.4) with postsynaptic mGluR6 receptors. We show this coordination requires an extracellular protein, α2δ4, which complexes with CaV1.4 and the rod synaptogenic mediator, ELFN1, for trans-synaptic alignment with mGluR6. Eliminating α2δ4 in mice abolishes rod synaptogenesis and synaptic transmission to rod ON-bipolar cells, and disrupts postsynaptic mGluR6 clustering. We further find that in rods, α2δ4 is crucial for organizing synaptic ribbons and setting CaV1.4 voltage sensitivity. In cones, α2δ4 is essential for CaV1.4 function, but is not required for ribbon organization, synaptogenesis, or synaptic transmission. These findings offer insights into retinal pathologies associated with α2δ4 dysfunction.

Keywords: calcium channels; cell adhesion; circuit formation; retina; ribbon synapse; synaptic transmission; synaptogenesis; trans-synaptic interactions; vision; wiring.

MeSH terms

  • Animals
  • Axons / physiology*
  • Calcium Channels / physiology*
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism
  • Calcium Channels, L-Type / physiology*
  • Cells, Cultured
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Nerve Tissue Proteins / metabolism
  • Receptors, Metabotropic Glutamate / physiology
  • Retinal Bipolar Cells / physiology
  • Retinal Cone Photoreceptor Cells / physiology
  • Retinal Rod Photoreceptor Cells / physiology*
  • Synapses / metabolism
  • Synaptic Transmission / physiology*


  • Cacna1f protein, mouse
  • Cacna2d4 protein, mouse
  • Calcium Channels
  • Calcium Channels, L-Type
  • Nerve Tissue Proteins
  • Receptors, Metabotropic Glutamate
  • extracellular leucine-rich repeat fibronectin containing 1 protein, mouse
  • metabotropic glutamate receptor 6