Age-related biophysical alterations of hippocampal pyramidal neurons: implications for learning and memory.

Normal brain aging is associated with deficits in learning and memory. The hippocampus, a structure critical for proper learning and memory functions, is frequently implicated in aging-related learning deficits. There are many reports of learning-related changes in hippocampal pyramidal neurons from animals that were trained in hippocampus-dependent learning paradigms. One consistent finding in hippocampal pyramidal neurons is a learning-related increase in postsynaptic neuronal excitability, resulting from a reduction in the postburst afterhyperpolarization (AHP). The hippocampus, as well as the ability to acquire hippocampus-dependent tasks, is particularly affected by aging. Correspondingly, hippocampal neurons also display an age-related decrease in excitability, resulting from an enhanced AHP. The correlation between neuronal excitability and learning ability strongly suggests that changes in the AHP are critically involved in learning and age-related learning deficits. Additional support for this argument comes from in vitro studies that examined the effect of compounds that facilitated learning in aging animals on the properties of CA1 pyramidal neurons. Many of these compounds increased the excitability of CA1 pyramidal neurons by reducing the AHP. Subsequent voltage-clamp recordings showed that AHP reduction by these compounds mainly reflects the reduction of two of its currents, the I(AHP) and the sI(AHP). Conversely, age-related AHP enhancements primarily impact the I(AHP) and the sI(AHP). Given that the I(AHP) accounts for a small portion of the total AHP, and that the sI(AHP) is the AHP current that most critically modulates neuronal excitability, changes in neuronal excitability seen in learning and in aging are predominantly caused by changes in the sI(AHP). The fact that the sI(AHP) receives neuromodulation from many transmitter systems important for learning and sensitive to aging lends further support for its role in age-related learning deficits. In this article, we review: (1) two hippocampus-dependent learning tasks, trace eyeblink conditioning and Morris water maze training, that are used extensively in our laboratory to examine learning and aging-related learning deficits; (2) aging-related changes in several important neurotransmitter systems, and how the these changes impact learning and memory functions during aging; and (3) changes in the AHP and the sI(AHP) in hippocampal pyramidal neurons in relation to compromised neurotransmission, as well as to learning, in aging animals. The correlations between a reduction in the sI(AHP) in learning, and an enhancement in the sI(AHP) in aging provide compelling evidence that this current plays a critical role in cognitive functions, and further suggest that the key modulators of the AHP are good candidates for future therapeutic interventions in age-related neurodegenerative diseases.