Calcium dynamics change in degenerating cone photoreceptors

Abstract

Cone photoreceptors (cones) are essential for high-resolution daylight vision and colour perception. Loss of cones in hereditary retinal diseases has a dramatic impact on human vision. The mechanisms underlying cone death are poorly understood, and consequently, there are no treatments available. Previous studies suggest a central role for calcium (Ca²⁺) homeostasis deficits in photoreceptor degeneration; however, direct evidence for this is scarce and physiological measurements of Ca²⁺ in degenerating mammalian cones are lacking.Here, we took advantage of the transgenic HR2.1:TN-XL mouse line that expresses a genetically encoded Ca²⁺ biosensor exclusively in cones. We cross-bred this line with mouse models for primary ("cone photoreceptor function loss-1", cpfl1) and secondary ("retinal degeneration-1", rd1) cone degeneration, respectively, and assessed resting Ca²⁺ levels and light-evoked Ca²⁺ responses in cones using two-photon imaging. We found that Ca²⁺ dynamics were altered in cpfl1 cones, showing higher noise and variable Ca²⁺ levels, with significantly wider distribution than for wild-type and rd1 cones. Unexpectedly, up to 21% of cpfl1 cones still displayed light-evoked Ca²⁺ responses, which were larger and slower than wild-type responses. In contrast, genetically intact rd1 cones were characterized by lower noise and complete lack of visual function.Our study demonstrates alterations in cone Ca²⁺ dynamics in both primary and secondary cone degeneration. Our results are consistent with the view that higher (fluctuating) cone Ca²⁺ levels are involved in photoreceptor cell death in primary (cpfl1) but not in secondary (rd1) cone degeneration. These findings may guide the future development of therapies targeting photoreceptor Ca²⁺ homeostasis.