Senescent neurophysiology: Ca²⁺ signaling from the membrane to the nucleus

The current review provides a historical perspective on the evolution of hypothesized mechanisms for senescent neurophysiology, focused on the CA1 region of the hippocampus, and the relationship of senescent neurophysiology to impaired hippocampal-dependent memory. Senescent neurophysiology involves processes linked to calcium (Ca²⁺) signaling including an increase in the Ca²⁺-dependent afterhyperpolarization (AHP), decreasing pyramidal cell excitability, hyporesponsiveness of N-methyl-D-aspartate (NMDA) receptor function, and a shift in Ca²⁺-dependent synaptic plasticity. Dysregulation of intracellular Ca²⁺ and downstream signaling of kinase and phosphatase activity lies at the core of senescent neurophysiology. Ca²⁺-dysregulation involves a decrease in Ca²⁺ influx through NMDA receptors and an increase release of Ca²⁺ from internal Ca²⁺ stores. Recent work has identified changes in redox signaling, arising in middle-age, as an initiating factor for senescent neurophysiology. The shift in redox state links processes of aging, oxidative stress and inflammation, with functional changes in mechanisms required for episodic memory. The link between age-related changes in Ca²⁺ signaling, epigenetics and gene expression is an exciting area of research. Pharmacological and behavioral intervention, initiated in middle-age, can promote memory function by initiating transcription of neuroprotective genes and rejuvenating neurophysiology. However, with more advanced age, or under conditions of neurodegenerative disease, epigenetic changes may weaken the link between environmental influences and transcription, decreasing resilience of memory function.