Biophysical alterations of hippocampal pyramidal neurons in learning, ageing and Alzheimer's disease.

A series of behavioral, electrophysiological, and molecular biochemical experiments are reviewed indicating that when animals learn hippocampus-dependent tasks, output neurons in the CA1 and CA3 hippocampal subfields show reductions in the slow, post-burst afterhyperpolarization (AHP). The slow AHP is mediated by an apamin-insensitive calcium-activated potassium current. A reduction in the slow AHP makes hippocampal neurons more excitable and facilitates NMDA receptor-mediated response and temporal summation. During normal aging and in a mouse model of Alzheimer's disease (AD), the slow AHP is increased, making neurons less excitable and making learning more difficult. The subgroup of aging animals that are able to learn demonstrates the capacity to increase neuronal excitability by reducing the size of the slow AHP. Similarly, in a mouse model of AD, mice that are able to learn normally after a genetic alteration have a normal capacity for increasing hippocampal neuron excitability by reducing their slow AHP. We suggest that reduction in the slow AHP is basic to learning in young and aging animals. Inability to modulate the slow AHP contributes to learning deficits that occur during aging and early stages of AD.