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

Neuronal intracellular Ca homeostasis is critical to the normal physiological functions of neurons and neuronal Ca 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 levels stimulate the dysregulation of intracellular signaling, which subsequently induces neuronal cell death. We examined intracellular Ca homeostasis in cortical ( and hippocampal ( 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]) in cortical () and hippocampal () neurons associated with increased hippocampal neuronal calpain activity and reduced cell viability. , removal of extracellular Ca or treatment with SAR7334 or dantrolene reduced [Ca] in all age groups and dantrolene treatment lowered calpain activity and increased cell viability. , 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 dyshomeostasis is a major mechanism underlying the cognitive deficits seen in both normal aging and degenerative neurologic diseases.