FUNCTIONAL-ASPECTS OF CALCIUM-CHANNEL MODULATION

Associative learning is accompanied by a number of changes in the brai n, many mediated by calcium. We have used eyeblink conditioning, a wel l-controlled learning task in animals and humans, to elucidate these c hanges. Our studies have focused on the hippocampus, a temporal lobe s tructure known to be important for storage of new information during l earning in mammalian brain. Hippocampal neurons show an enhanced firin g rate during learning cor-related with behavioral acquisition; they a lso show reduction in a calcium-mediated after-hyperpolarization (AHP) , a likely mechanism for their enhanced activity. Aging animals and hu mans exhibit learning deficits; aging hippocampal neurons show increas ed AHPs and altered calcium buffering, which contribute to the behavio ral learning deficits. Intravenous administration of the calcium antag onist nimodipine causes aging rabbits to learn the eyeblink conditioni ng task as quickly as young controls. Oral nimodipine enhances learnin g rates in aging rabbits, rats, and monkeys. In each case, the type of learning task analyzed is dependent on hippocampal processing for acq uisition and is impaired with aging. Nimodipine also reverses aging-re lated alterations in open field behavior of both rats and rabbits. We have done a series of physiological studies focused on the possible ro le of nimodipine in enhancing neuronal activity in the hippocampus of aging rabbits. The purpose of these studies was to determine how nimod ipine may be functioning at a cellular level to increase the learning rate. Four major conclusions may be drawn from our data: (a) Nimodipin e strongly enhanced the firing rate of single hippocampal pyramidal ne urons recorded in vivo in an aging- and concentration-dependent fashio n. 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 a n outward calcium-activated potassium current, was markedly larger in pyramidal neurons in hippocampal slices prepared from aging rabbits. N imodipine, at concentrations as low as 100 nM, reliably reduced the AH Ps of aging pyramidal cells. Aging neurons also showed more spike freq uency adaptation, or accomodation, than young neurons. Nimodipine part ially blocked accomodation 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 conc entration-dependent fashion; concentrations as low as 100 nM reduced t he calcium action potential in aging CA1 neurons without effects on yo ung cells. (d) Nimodipine blocked the high threshold. noninactivating calcium current (L-type calcium current) in acutely dissociated hippoc ampal pyramidal neurons. This effect quickly washed out and was revers ed with application of Bay K 8644, a dihydropyrdine calcium-channel ag onist. These data, gathered both in vivo and in vitro, suggest that ni modipine acts directly on neuronal elements known to be importantly in volved in eyeblink conditioning. Such direct neuronal action should he lp to improve learning in aging brain. The clinical implications of ou r work lie in the attempt to use nimodipine to treat Alzheimer disease or learning deficits in the aging. Many of the learning deficits in a ging human brain may be importantly mediated by excess neuronal calciu m and should be amenable to intervention with a calcium-channel antago nist.