Zhang, Y., P. L. Carlen, and L. Zhang. Kinetics of muscarinic reduction of I _sAHP in hippocampal neurons: effects of acetylcholinesterase inhibitors. J. Neurophysiol. 78: 2999–3007, 1997. The present experiments were designed to elucidate the time frame in which an evoked cholinergic impulse decreases the Ca²⁺-dependent K⁺ current ( I _sAHP) in hippocampal CA1 neurons, and to determine to what extent acetylcholinesterase (AChE) inhibitors enhance the efficacy of the cholinergic impulse. Whole cell voltage-clamp recordings were performed on hippocampal CA1 neurons of rat brain slices and I _sAHPs were evoked by constant depolarizing pulses. Cholinergic afferent fibers in stratum oriens were stimulated electrically and the time interval between the afferent stimulus and the depolarizing pulse was varied from 1 to 30 s. In slices perfused with the standard external medium, the afferent stimulus caused a profound decrease in the following I _sAHP only when the stimulus preceded the depolarizing pulse by 1–2 s. The stimulus was without effects on the I _sAHP when applied ≥5s before the depolarizing pulse. The effects of the afferent stimulus were greatly enhanced in CA1 neurons exposed to the catalytic AChE inhibitors neostigmine, physostigmine, or 9-amino-1,2,3,4-tetrahydro-acridine. A substantial decrease in the I _sAHP was observed even when the stimulus preceded the depolarizing pulse by ≥30 s. However applications of peripheral site AChE inhibitors decamethonium and propidium caused only minor or no enhancement of the I _sAHP reduction after the afferent stimulus. We suggest in physiological conditions that muscarinic modulation of ionic conductances of CNS neurons has a limited time course after a cholinergic impulse and that the modulation is greatly enhanced and prolonged when catalytic activities of AChEs are suppressed pharmacologically.