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, Olivier Thibault

Research output: Contribution to journalArticlepeer-review

147 Scopus citations

Abstract

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 Ca 2+ 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 Ca 2+ 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.

Original languageEnglish
Pages (from-to)3482-3490
Number of pages9
JournalJournal of Neuroscience
Volume26
Issue number13
DOIs
StatePublished - Mar 29 2006

Keywords

  • Afterhyperpolarization
  • Aging
  • Calcium channels
  • Calcium imaging
  • Endoplasmic reticulum
  • Ryanodine

ASJC Scopus subject areas

  • Neuroscience (all)

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