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

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 (Ca(V)1.4) with postsynaptic mGluR6 receptors. We show this coordination requires an extracellular protein, alpha 2 delta 4, which complexes with Ca(V)1.4 and the rod synaptogenic mediator, ELFN1, for trans-synaptic alignment with mGluR6. Eliminating alpha 2 delta 4 in mice abolishes rod synaptogenesis and synaptic transmission to rod ONbipolar cells, and disrupts postsynaptic mGluR6 clustering. We further find that in rods, alpha 2 delta 4 is crucial for organizing synaptic ribbons and setting Ca(V)1.4 voltage sensitivity. In cones, alpha 2 delta 4 is essential for Ca(V)1.4 function, but is not required for ribbon organization, synaptogenesis, or synaptic transmission. These findings offer insights into retinal pathologies associated with alpha 2 delta 4 dysfunction.