Early and Simultaneous Emergence of Multiple Hippocampal Biomarkers of Aging Is Mediated by Ca2+-induced Ca2+ Release

J Neurosci. 2006 Mar 29;26(13):3482-90. doi: 10.1523/JNEUROSCI.4171-05.2006.

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 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.

Publication types

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

MeSH terms

  • Aging / physiology*
  • Animals
  • Biomarkers / metabolism
  • Calcium / metabolism*
  • Calcium Channels, L-Type / metabolism*
  • Calcium Signaling / physiology*
  • Cells, Cultured
  • Hippocampus / physiology*
  • Homeostasis / physiology
  • Ion Channel Gating
  • Male
  • Neurons / physiology*
  • Rats
  • Rats, Inbred F344
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Signal Transduction / physiology

Substances

  • Biomarkers
  • Calcium Channels, L-Type
  • Ryanodine Receptor Calcium Release Channel
  • Calcium