Knockout of CaV1.3 L-type calcium channels in a mouse model of retinitis pigmentosa

Irem Kilicarslan,Alexandra Koschak,Lucia Zanetti,Christoph Schwarzer,Enrica Strettoi,Elena Novelli

doi:10.1038/s41598-021-94304-3

Abstract

Retinitis Pigmentosa is a genetically heterogeneous, degenerative retinal disorder characterized by gradual dysfunction and death of photoreceptors, first rods and later cones, and progressive blindness. Studies suggested that application of L-type calcium channel blockers rescues photoreceptors in paradigms related to Ca2+ overflow. To investigate whether Cav1.3 L-type channels have protective effects in the retina, we established a new mouse model by crossing rd10, modeling autosomal-recessive RP, with Cav1.3 deficient mice (rd10/Cav1.3KO). Our immunohistochemical analyses revealed an influence of Cav1.3 channels on the degenerative process of photoreceptors. The absence of Cav1.3 delayed the centre-to-periphery degeneration of rods indicated by a significantly higher number of photoreceptor rows and, consequently, of cones. In accordance with a preserved number of cones we observed a regular row of cone somas in rd10/Cav1.3-KO retinas. Surviving rod photoreceptors maintained synaptic contacts with rod bipolar cells. However, the delay in degeneration was only observed up to postnatal day 45. Although we observed a reduction in the spontaneous oscillatory retinal activity during multielectrode array analyses, measurable functional preservation was lacking in behavioural tests. In conclusion, Cav1.3 channels contribute to photoreceptor degeneration in rd10 retinas but photoreceptor temporary rescue might rather be achieved indirectly through other retinal cell layers.

Highlights

Retinitis Pigmentosa is a genetically heterogeneous, degenerative retinal disorder characterized by gradual dysfunction and death of photoreceptors, first rods and later cones, and progressive blindness
This study investigated the effect of a Cav1.3 L-type Ca2+ channels (LTCCs) knockout in the rd[10] mouse model of Retinitis pigmentosa (RP)
Previous studies suggested that LTCC blockage or genetic ablation could rescue photoreceptor function in paradigms of RP caused by Ca2+ overflow[27,36]

Summary

Introduction

Retinitis Pigmentosa is a genetically heterogeneous, degenerative retinal disorder characterized by gradual dysfunction and death of photoreceptors, first rods and later cones, and progressive blindness. Blocking Ca2+ currents mediated by Cav1.4 might be counterproductive for restoring vision because Cav1.4-KO mice are functionally blind[28], and humans with mutations in the CACNA1F gene encoding Cav1.4 channels suffer from congenital stationary night blindness type 2 (OMIM 300071, for r eview[29]). The study supported a role for LTCC mediated C a2+ influx in the degenerative process of the disease and a short-term preservation of photoreceptors in the rd[1] mouse following genetic deletion of the synaptic Cav1.4 channels[27]. We chose Cav1.3 for our study because Cav1.3 deficiency does not lead to detectable changes in the basic retinal architecture and does not alter the distribution of Cav1.4 in the retina[31] Both the scotopic and photopic ERG of Cav1.3-KO mice show only a slightly reduced b-wave, allowing us to exclude a major visual dysfunction. Our data showed that Cav1.3 contributes to the photoreceptor cell death, its elimination is not sufficient to restore retinal function

Methods

Results

Conclusion