| Previous studies have demonstrated that postburst afterhyperpolarization (AHP) and spike-frequency adaptation (accommodation) of CA1 hippocampal pyramidal neurons are (1) enhanced in neurons from aging rabbits and rats in vitro as compared to those from young animals; and (2) reduced in neurons from rabbits that have learned a temporal, hippocampus-dependent trace eyeblink conditioning task (tEBC). Additionally, it has been shown that aging subjects (rabbits, rats, humans) are impaired in learning tEBC. This age-related learning impairment is ameliorated by treatment with pharmacological compounds, that among other things, reduce AHP and accommodation of CA1 hippocampal pyramidal neurons in vitro.; The present findings provide strong support that AHP reduction in CA1 neurons is a cellular substrate of learning. AHP reduction in CA1 neurons was observed in rats that learned the spatial, hippocampus-dependent watermaze task, and was prominent in neurons from dorsal hippocampus, the region crucial for learning this task. The AHP reduction of CA1 neurons was a learning related phenomenon, as rats that failed to learn the task had CA1 neurons with AHPs nearly identical to controls. The AHP reduction in CA1 neurons was also observed in rats that learned tEBC. Therefore, AHP reduction in CA1 neurons is a cellular substrate of learning that is conserved across species and tasks.; Age-related enhancements of AHP and accommodation in CA1 neurons were reversed by cholinesterase inhibitors (potential therapeutic compounds for Alzheimer's disease (AD); metrifonate and galanthamine). These two compounds and apamin that also reduced the AHP and accommodation of CA1 neurons have been previously reported to reverse learning deficits caused by either hippocampal lesions or normal aging in animals. Both cholinesterase inhibitors have been shown to lessen learning deficits of patients with AD. Thus, it may be possible that reductions of AHP and accommodation in hippocampal pyramidal neurons by pharmaceutical interventions lead to the amelioration of learning deficits observed in aging animals, and perhaps even ameliorate some of the symptoms of AD.; These results suggest that the reductions of AHP and accommodation of CA1 neurons may be a cellular substrate of learning, and the enhancements of these measures with normal aging may be one of the key phenomenon that underlie age-related learning deficits. |
