Early and simultaneous emergence of multiple hippocampal biomarkers of aging is mediated by Ca²⁺-induced Ca²⁺ release

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.