Confirming a prediction of the calcium hypothesis of photoreceptor aging in mice

Neurobiol Aging. 2014 Aug;35(8):1883-91. doi: 10.1016/j.neurobiolaging.2014.02.020. Epub 2014 Mar 2.


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.

Keywords: Aging; MEMRI; OKT; Retina.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / metabolism
  • Aging / pathology
  • Aging / physiology*
  • Animals
  • Calcium Channels, L-Type / metabolism
  • Calcium Channels, L-Type / physiology*
  • Color Vision / physiology*
  • Diltiazem / metabolism
  • Diltiazem / pharmacology
  • Magnetic Resonance Imaging / methods
  • Male
  • Manganese / metabolism
  • Mice, Inbred C57BL
  • Photoreceptor Cells, Vertebrate / metabolism
  • Photoreceptor Cells, Vertebrate / physiology*
  • Rats
  • Retina / drug effects
  • Retina / metabolism
  • Retina / pathology
  • Retinal Cone Photoreceptor Cells / physiology
  • Retinal Rod Photoreceptor Cells / physiology


  • Calcium Channels, L-Type
  • Manganese
  • Diltiazem