Impaired frequency potentiation as a basis for aging-dependent memory impairment: The role of excess calcium influx

Frequency potentiation (FP), the growth of synaptic responses during repetitive synaptic activation, has been found consistently to be impaired in hippocampus of aged rats. This impairment has also been found to be correlated with aging-impaired learning/memory processes. Quantitative ultrastructural analyses indicate that reduced synaptic vesicle attachment to active release zones, rather than vesicle depletion, is associated with impaired FP. Postsynaptic factors such as an increased afterhyperpolarization also appear to be involved. Excess calcium influx impairs FP (in contrast to its enhancing effect on long-term potentiation), and an extensive series of studies has indicated that elevated voltage-dependent calcium influx occurs in hippocampal pyramidal neurons of aged animals. Intracellular voltage recordings and voltage-clamp analyses indicate that dihydropyridine-sensitive (L-type) calcium channels, and perhaps N-type channels, are altered by aging, thereby resulting in impaired function (and possibly, in gradual neurodegeneration).