In healthy aging, visual function declines throughout adulthood. Age-related changes in neuronal ion homeostasis — specifically, increased Ca2+ influx through L-type voltage gated calcium channels (L-VGCCs) — are believed to contribute to certain functional declines, but this possibility has not yet been tested in the neural retina. In young, mid- and old adult Long-Evans rats, we compared visual function (optokinetic tracking), as well as retinal physiology and eye morphology (Mn2+-enhanced MRI (MEMRI), which uses neuronal (Mn2+ uptake as a marker of Ca2+ influx). We documented significant age-related decreases in visual performance and increases in retinal ion influx. We confirmed that (Mn2+ uptake was regulated by L-VGCC using systemic and topical application of the L-VGCC antagonist nifedipine, and discovered an age-related change in sensitivity to L-VGCC blocker diltiazem. Based on Western blot studies, we find this sensitivity change to be consistent with the age-dependant appearance of drug-insensitive L-VGCC isoforms. Longitudinally, rats starting the study with relatively high retinal Mn2+ uptake, compared to other cohort members, experienced significantly greater declines in contrast sensitivity in the ∼4.5 mo following MRI. Independent of that relationship, rats starting the study with relatively large eyes experienced significantly greater declines in contrast sensitivity. The latter finding suggests that particularly rapid juvenile or young-adult growth is a risk factor for particularly rapid senescence. Longitudinally, we found no evidence of retinal volume loss, and found that changes in retinal volume were not correlated with changes in visual function — suggesting that age-related vision declines cannot be explained by neuron loss. In summary, our longitudinal studies identify two previously-unknown risk factors for age-related vision declines: rapid eye growth in early life, and age-related changes in L-VGCC-dependent retinal ion physiology.
|Advisor:||Berkowitz, Bruce A.|
|Commitee:||Goebel, Dennis J., Lustig, Cindy A., Walker, Paul D.|
|School:||Wayne State University|
|Department:||Anatomy and Cell Biology|
|School Location:||United States -- Michigan|
|Source:||DAI-B 74/09(E), Dissertation Abstracts International|
|Keywords:||Healthy aging, Manganese-enhanced MRI, Retina, Vision loss|
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