Memory and Learning Deficits Are Associated With Ca 2+ Dyshomeostasis in Normal Aging.

Neuronal intracellular Ca ²⁺ homeostasis is critical to the normal physiological functions of neurons and neuronal Ca ²⁺ dyshomeostasis has been associated with the age-related decline of cognitive functions. Accumulated evidence indicates that the underlying mechanism for this is that abnormal intracellular Ca ²⁺ levels stimulate the dysregulation of intracellular signaling, which subsequently induces neuronal cell death. We examined intracellular Ca ²⁺ homeostasis in cortical ( in vivo) and hippocampal ( in vitro) neurons from young (3-months), middle-age (12-months), and aged (24-months) wild type C57BL6J mice. We found a progressive age-related elevation of intracellular resting calcium ([Ca ²⁺ ] _r ) in cortical ( in vivo ) and hippocampal ( in vitro ) neurons associated with increased hippocampal neuronal calpain activity and reduced cell viability. In vitro , removal of extracellular Ca ²⁺ or treatment with SAR7334 or dantrolene reduced [Ca ²⁺ ] _r in all age groups and dantrolene treatment lowered calpain activity and increased cell viability. In vivo , both middle-aged and aged mice showed cognitive deficits compared to young mice, which improved after dantrolene treatment. These findings support the hypothesis that intracellular Ca ²⁺ dyshomeostasis is a major mechanism underlying the cognitive deficits seen in both normal aging and degenerative neurologic diseases.
(Copyright © 2020 Uryash, Flores, Adams, Allen and Lopez.)