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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 squirrels, 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., Competing Interests: JM, GO, Jd, AH, CG, SW, KR, DF, NS, DM, BZ, SD, MH, AL No competing interests declared, (© 2024, Maddox, Ordemann et al.)

Synapses are fundamental information processing units that rely on voltage-gated Ca 2+ (Ca v ) channels to trigger Ca 2+ -dependent neurotransmitter release. Ca v channels also play Ca 2+ -independent roles in other biological contexts, but whether they do so in axon terminals is unknown. Here, we addressed this unknown with respect to the requirement for Ca v 1.4 L-type channels for the formation of rod photoreceptor synapses in the retina. Using a mouse strain expressing a non-conducting mutant form of Ca v 1.4, we report that the Ca v 1.4 protein, but not its Ca 2+ conductance, is required for the molecular assembly of rod synapses; however, Ca v 1.4 Ca 2+ signals are needed for the appropriate recruitment of postsynaptic partners. Our results support a model in which presynaptic Ca v channels serve both as organizers of synaptic building blocks and as sources of Ca 2+ ions in building the first synapse of the visual pathway and perhaps more broadly in the nervous system., Competing Interests: JM, KR, RY, BW, JH, PD, VK, LD, SB, NA, MH, AL No competing interests declared, (© 2020, Maddox et al.)