A non-conducting role of the Ca(v)1.4 Ca(2+) channel drives homeostatic plasticity at the cone photoreceptor synapse.

In congenital stationary night blindness type 2 (CSNB2)-a disorder involving the Ca(v)1.4 (L-type) Ca(2+) channel-visual impairment is mild considering that Ca(v)1.4 mediates synaptic release from rod and cone photoreceptors. Here, we addressed this conundrum using a Ca(v)1.4 knockout (KO) mouse and a knock-in (G369i KI) mouse expressing a non-conducting Ca(v)1.4. Surprisingly, Ca(v)3 (T-type) Ca(2+) currents were detected in cones of G369i KI mice and Ca(v)1.4 KO mice but not in cones of wild-type mouse, ground squirrel, and macaque retina. Whereas Ca(v)1.4 KO mice are blind, G369i KI mice exhibit normal photopic (i.e., cone-mediated) visual behavior. Cone synapses, which fail to form in Ca(v)1.4 KO mice, are present, albeit enlarged, and with some errors in postsynaptic wiring in G369i KI mice. While Ca(v)1.4 KO mice lack evidence of cone synaptic responses, electrophysiological recordings in G369i KI mice revealed nominal transmission from cones to horizontal cells and bipolar cells. In CSNB2, we propose that Ca(v)3 channels maintain cone synaptic output provided that the nonconducting role of Ca(v)1.4 in cone synaptogenesis remains intact. Our findings reveal an unexpected form of homeostatic plasticity that relies on a non-canonical role of an ion channel.