Function of cone and cone-related pathways in CaV1.4 IT mice

• Published in: Scientific reports Vol. 11; no. 1; pp. 1 - 15
• Main Authors: Zanetti, Lucia, Kilicarslan, Irem, Netzer, Michael, Babai, Norbert, Seitter, Hartwig, Koschak, Alexandra
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/378; 692/699/3161/3175/3188; Bipolar cells; Blindness; Calcium channels; Calcium channels (L-type); Calcium channels (voltage-gated); Calcium influx; Cones; Ganglion cells; Horizontal cells; Humanities and Social Sciences; Morphology; multidisciplinary; Mutation; Nyctalopia; Photoreceptors; Science; Science (multidisciplinary); Stationary night blindness; Synaptic transmission; Toxicity
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-82210-7

Ca V 1.4 L-type calcium channels are predominantly expressed in photoreceptor terminals playing a crucial role for synaptic transmission and, consequently, for vision. Human mutations in the encoding gene are associated with congenital stationary night blindness type-2. Besides rod-driven scotopic vision also cone-driven photopic responses are severely affected in patients. The present study therefore examined functional and morphological changes in cones and cone-related pathways in mice carrying the Ca V 1.4 gain-of function mutation I756T (Ca V 1.4-IT) using multielectrode array, patch-clamp and immunohistochemical analyses. Ca V 1.4-IT ganglion cell responses to photopic stimuli were seen only in a small fraction of cells indicative of a major impairment in the cone pathway. Though cone photoreceptors underwent morphological rearrangements, they retained their ability to release glutamate. Our functional data suggested a postsynaptic cone bipolar cell defect, supported by the fact that the majority of cone bipolar cells showed sprouting, while horizontal cells maintained contacts with cones and cone-to-horizontal cell input was preserved. Furthermore a reduction of basal Ca 2+ influx by a calcium channel blocker was not sufficient to rescue synaptic transmission deficits caused by the Ca V 1.4-IT mutation. Long term treatments with low-dose Ca 2+ channel blockers might however be beneficial reducing Ca 2+ toxicity without major effects on ganglion cells responses.