Functional Aspects of Calcium-Channel Modulation

Abstract

Associative learning is accompanied by a number of changes in the brain, many mediated by calcium. We have used eyeblink conditioning, a well-controlled learning task in animals and humans, to elucidate these changes. Our studies have focused on the hippocampus, a temporal lobe structure known to be important for storage of new information during learning in mammalian brain. Hippocampal neurons show an enhanced firing rate during learning correlated with behavioral acquisition; they also show reduction in a calcium-mediated after-hyperpolarization (AHP), a likely mechanism for their enhanced activity. Aging animals and humans exhibit learning deficits; aging hippocampal neurons show increased AHPs and altered calcium buffering, which contribute to the behavioral learning deficits. Intravenous administration of the calcium antagonist nimodipine causes aging rabbits to learn the eyeblink conditioning task as quickly as young controls. Oral nimodipine enhances learning rates in aging rabbits, rats, and monkeys. In each case, the type of learning task analyzed is dependent on hippocampal processing for acquisition and is impaired with aging. Nimodipine also reverses aging-related alterations in open field behavior of both rats and rabbits. We have done a series of physiological studies focused on the possible role of nimodipine in enhancing neuronal activity in the hippocampus of aging rabbits. The purpose of these studies was to determine how nimodipine may be functioning at a cellular level to increase the learning rate. Four major conclusions may be drawn from our data: (a) Nimodipine strongly enhanced the firing rate of single hippocampal pyramidal neurons recorded in vivo in an aging- and concentration-dependent fashion. Other calcium-channel blockers, such as nifedipine and flunarizine, given to control for cerebral blood flow changes, had essentially no effect on the hippocampal firing rate. (b) The slow AHP, mediated by an outward calcium-activated potassium current, was markedly larger in pyramidal neurons in hippocampal slices prepared from aging rabbits. Nimodipine, at concentrations as low as 100 nM, reliably reduced the AHPs of aging pyramidal cells. Aging neurons also showed more spike frequency adaptation, or accommodation, than young neurons. Nimodipine partially blocked accommodation at concentrations as low as 10 nM in aging neurons. (c) The calcium action potential was larger in aging neurons. Nimodipine modulated the calcium action potential in an age- and concentration-dependent fashion; concentrations as low as 100 nM reduced the calcium action potential in aging CA1 neurons without effects on young cells. (d) Nimodipine blocked the high threshold, noninactivating calcium current (L-type calcium current) in acutely dissociated hippocampal pyramidal neurons.(ABSTRACT TRUNCATED AT 400 WORDS)