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 dysfunction of the Ca v 1.4 Ca 2+ channel-visual impairment is relatively mild considering that Ca v 1.4 mediates synaptic transmission by rod and cone photoreceptors. Here, we addressed this conundrum using a Ca v 1.4 knockout (KO) mouse and a knock-in (KI) mouse expressing a non-conducting Ca v 1.4 mutant. Surprisingly, aberrant Ca v 3 currents were detected in cones of the KI and KO but not wild-type mice. Cone synapses, which fail to develop in KO mice, are present but enlarged in KI mice. Moreover, light responses in cone pathways and photopic visual behavior are preserved in KI but not in KO mice. In CSNB2, we propose that Ca v 3 channels maintain cone synaptic output provided that the Ca 2+ -independent 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.