A non-conducting role of the Ca_v1.4 Ca²⁺ channel drives homeostatic plasticity at the cone photoreceptor synapse.

Abstract

In congenital stationary night blindness, type 2 (CSNB2)-a disorder involving the Ca_v1.4 (L-type) Ca²⁺ channel-visual impairment is mild considering that Ca_v1.4 mediates synaptic release from rod and cone photoreceptors. Here, we addressed this conundrum using a Ca_v1.4 knockout (KO) mouse and a knock-in (G369i KI) mouse expressing a non-conducting Ca_v1.4. Surprisingly, Ca_v3 (T-type) Ca²⁺ currents were detected in cones of G369i KI mice and Ca_v1.4 KO mice but not in cones of wild-type mouse, ground squirrels, and macaque retina. Whereas Ca_v1.4 KO mice are blind, G369i KI mice exhibit normal photopic (i.e. cone-mediated) visual behavior. Cone synapses, which fail to form in Ca_v1.4 KO mice, are present, albeit enlarged, and with some errors in postsynaptic wiring in G369i KI mice. While Ca_v1.4 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_v3 channels maintain cone synaptic output provided that the nonconducting role of Ca_v1.4 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.