Metrifonate decreases sI(AHP) in CA1 pyramidal neurons in vitro

Metrifonate, a cholinesterase inhibitor, has been shown to enhance learning in aging rabbits and rats, and to alleviate the cognitive deficits observe d in Alzheimer's disease patients. We have previously determined that bath application of metrifonate reduces the spike frequency adaptation and postb urst after-hyperpolarization (AHP) in rabbit CA1 pyramidal neurons in vitro using sharp electrode current-clamp recording. The postburst AHP and accom modation observed in current clamp are the result of four slow outward pota ssium currents (sI(AHP), I-AHP, I-M, and I-C) and the hyperpolarization act ivated mixed cation current, 1(h). We recorded from visually identified CA1 hippocampal pyramidal neurons in vitro using whole cell voltage-clamp tech nique to better isolate and characterize which component currents of the AH P are affected by metrifonate. We observed an age-related enhancement of th e slow component of the AHP tail current (sI(AHP)), but not of the fast dec aying component of the AHP tail current (I-AHP, I-M, and I-C). Bath perfusi on of metrifonate reduced sI(AHP) at concentrations that cause a reduction of the AHP and accommodation in current-clamp recordings, with no apparent reduction of I-AHP, I-M, and I-C. The functional consequences of metrifonat e administration are apparently mediated solely through modulation of the s I(AHP).