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 observed in Alzheimer's disease patients. We have previously determined that bath application of metrifonate reduces the spike frequency adaptation and postburst afterhyperpolarization (AHP) in rabbit CA1 pyramidal neurons in vitro using sharp electrode current-clamp recording. The postburst AHP and accommodation observed in current clamp are the result of four slow outward potassium currents (sI_AHP, I_AHP, I_M, and I_c) and the hyperpolarization activated mixed cation current, I_h. We recorded from visually identified CA1 hippocampal pyramidal neurons in vitro using whole cell voltage-clamp technique to better isolate and characterize which component currents of the AHP are affected by metrifonate. We observed an age-related enhancement of the slow component of the AHP tail current (sI_AHP), but not of the fast decaying component of the AHP tail current (I_AHP, I_M, and I_C). Bath perfusion 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 metrifonate administration are apparently mediated solely through modulation of the sI_AHP.