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Manoj Mohan Kulkarni, Robin Kemmler, Bernd Wissinger, Thomas Euler, Francois Paquet-Durand; Calcium dynamics in dying cone photoreceptors. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1260.
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© ARVO (1962-2015); The Authors (2016-present)
Cone photoreceptors are the main source of human sight, enabling color and high-resolution daylight vision. In inherited retinal diseases, loss of cones may occur primarily or secondarily, depending on whether the initial genetic defect affects cone or rod photoreceptors. Here, we used cpfl1 mice, carrying a mutation in the cone specific Pde6c gene, and rd1 mice with a mutation in the rod specific Pde6b gene, as models for primary and secondary cone degeneration, respectively. Since, it has been speculated that both primary and secondary cone degeneration may be caused by a cytotoxic overload of Ca2+, we set out to study cone Ca2+ dynamics using 2-photon imaging and transgenic mice which express the HR2.1:TN-XL Ca2+ biosensor in cones (Wei et al., J Neurosci. 32:6981-94; 2012).
Ca2+ imaging was performed on wild-type/TN-XL, as well as on cpfl1/TN-XL and rd1/TN-XL crossbred animals. Different staining techniques (TUNEL assay, cGMP immunofluorescence, calpain activity assay) were used to further characterize cone degeneration.
Abnormal cGMP increases in cones, a presumed telltale for Ca2+ accumulation, occurred only during primary, but not during secondary cone degeneration. At post-natal day 30, genetically intact cones in rd1/TN-XL retina showed no Ca2+ response when stimulated by light, while a substantial number of mutant cpfl1/TN-XL cones still displayed light responses. Accordingly, significant difference in relative Ca2+ levels distribution was detected between cpfl1/TN-XL and rd1/TN-XL cones. Currently we perform calibrated Ca2+ measurements to evaluate absolute cone Ca2+ levels in the three mouse lines.
The HR2.1: TN-XL Ca2+ biosensor mouse line allows studying cone Ca2+ regulation, not only with pharmacological manipulations but also in genetic mutants. The observed light-evoked responses in cpfl1/TN-XL suggest residual cone PDE6 activity. Our preliminary data suggest dysfunctional Ca2+ regulation during primary (cpfl1) but not in secondary (rd1) cone degeneration. Therefore, modulation of Ca2+ signaling may be a suitable target for neuroprotection therapy in primary cone degeneration.
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