title: Confirming a prediction of the calcium hypothesis of photoreceptor aging in mice.
abstract: Prior work in healthy rats supported a calcium hypothesis of photoreceptor aging, wherein progressive age-related declines in photopic vision are explainable by the extent of earlier escalating d-cis-diltiazem-insensitive increases in photoreceptor L-type calcium channel (LTCC) activity in vivo. Unlike rats, healthy mice have relatively stable photopic vision until after 18 months of age. We therefore hypothesized that photoreceptor LTCC activity in mice would not progressively increase until after 18 months. In 2-5, 10, 18, and 26 months male C57Bl/6J mice, photoreceptor LTCC activity and retinal thickness were evaluated in vivo (manganese-enhanced magnetic resonance imaging) with some groups also treated with d-cis-diltiazem; visual performance was evaluated (optokinetic tracking). Data were calibrated for cone-only responses using mice without rod transducin (GNAT1-/-). Photopic vision was stable until after 18 months without retinal thinning or progressive increases in retinal manganese uptake. We measured an uptake spike at 10 months. This spike, unlike that in the rat, was diltiazem sensitive in the dark and diltiazem insensitive in the light. Between dark and light, uptake in inner retina of older mice was unequal (unlike that in 2-5 months mice); outer retinal uptake was similar to that in 2-5 months mice. Stable murine photopic visual performance and nonescalating photoreceptor LTCC activity before 18 months of age were consistent with a prediction of the calcium hypothesis. Stark differences in the temporal evolution of mouse and rat photoreceptor LTCC activity suggest the need for personalized identification of the retinal mechanisms contributing to declines in photopic vision to ensure success of future treatment efforts.
authors.affiliation: Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA; Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: baberko@med.wayne.edu.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Berkowitz
authors.affiliation: Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Edmund Michael
authors.initials: EM
authors.lastname: Grady
authors.affiliation: Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Roberts
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism / Q000502:physiology*; D055253:Color Vision / Q000502:physiology*; D004110:Diltiazem / Q000378:metabolism / Q000494:pharmacology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008345:Manganese / Q000378:metabolism; D008810:Mice, Inbred C57BL; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology; D017948:Retinal Rod Photoreceptor Cells / Q000502:physiology
chemical_list: D020746:Calcium Channels, L-Type; D008345:Manganese; D004110:Diltiazem
keywords: Aging; MEMRI; OKT; Retina