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The Journal of Neuroscience, March 29, 2006, 26(13):3482-3490; doi:10.1523/JNEUROSCI.4171-05.2006

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Cellular/Molecular
Early and Simultaneous Emergence of Multiple Hippocampal Biomarkers of Aging Is Mediated by Ca²⁺-Induced Ca²⁺ Release

John C. Gant, Michelle M. Sama, Philip W. Landfield, and Olivier Thibault

Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, Kentucky 40536-0298

Correspondence should be addressed to Dr. Olivier Thibault, Department of Molecular and Biomedical Pharmacology, MS320, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536-0298. Email: othibau{at}uky.edu

Age-dependent changes in multiple Ca²⁺-related electrophysiological processes in the hippocampus appear to be consistent biomarkers of aging, and several also correlate with cognitive decline. These findings have led to the hypothesis that a common mechanism of Ca²⁺ dyshomeostasis underlies aspects of aging-dependent brain impairment. However, some key predictions of this view remain untested, including that multiple Ca²⁺-related biomarkers should emerge concurrently during aging and their onset should also precede/coincide with initial signs of cognitive decline. Moreover, blocking a putative common source of dysregulated Ca²⁺ should eliminate aging differences. Here, we tested these predictions using combined electrophysiological, imaging, and pharmacological approaches in CA1 neurons to determine the ages of onset (across 4-, 10-, 12-, 14-, and 23-month-old F344 rats) of several established biomarkers, including the increases in the slow afterhyperpolarization, spike accommodation, and [Ca²⁺]_i rise during repetitive synaptic stimulation. In addition, we tested the hypothesis that altered Ca²⁺-induced Ca²⁺ release (CICR) from ryanodine receptors, which can be triggered by L-type Ca²⁺ channels, provides a common source of dysregulated Ca²⁺ in aging. Results showed that multiple aging biomarkers were first detectable at about the same age (12 months of age; approximately midlife), sufficiently early to influence initial cognitive decline. Furthermore, selectively blocking CICR with ryanodine slowed the Ca²⁺ rise during synaptic stimulation more in aged rat neurons and, notably, reduced or eliminated aging differences in the biomarkers. Thus, this study provides the first evidence that altered CICR plays a role in driving the early and simultaneous emergence in hippocampus of multiple Ca²⁺-related biomarkers of aging.

Key words: aging; ryanodine; afterhyperpolarization; calcium imaging; calcium channels; endoplasmic reticulum

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Received Sept. 30, 2005; revised Feb. 16, 2006; accepted Feb. 16, 2006.

Correspondence should be addressed to Dr. Olivier Thibault, Department of Molecular and Biomedical Pharmacology, MS320, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536-0298. Email: othibau{at}uky.edu

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