Potentiation and suppression by eserine of muscarinic synaptic transmission in the guinea-pig hippocampal slice.

1. The effects of the anticholinesterase eserine on CA3 pyramidal cells and dentate gyrus granule cells in guinea-pig hippocampal slices were investigated with single-electrode current-clamp and voltage-clamp recording. 2. In the majority of cells superfused with eserine (0.5-10 microM) for 3-10 min, tetanic stimulation near the cell layers elicited a delayed depolarization (slow EPSP; duration up to 60 s) at a pre-stimulation membrane potential of -60 mV. The slow EPSP was blocked by atropine (1 microM). 3. Under voltage clamp at -60 mV holding potential, an apparent inward current (slow EPSC) with a similar time course to the slow EPSP was observed. 4. The amplitude of the delayed inward current was about 50 pA. The amplitude increased at holding potentials more positive than -60 mV. At holding potentials negative to -60 mV, the delayed inward current was too small to allow reliable analysis. In the absence of eserine, there was a delayed inward current, which was rather small, however, due to a superimposed outward current. 5. Eserine reduced the after-hyperpolarization following a train of action potentials. This effect was antagonized by atropine, but not to pirenzepine. In voltage-clamp recording, eserine reduced a current termed IAHP. 6. CA3 neurones treated with eserine exhibited a region of negative slope conductance (in tetrodotoxin). The slow inward current which developed at clamp potentials between -50 and -40 mV was reduced by Ni2+ (50 microM). The effect of eserine on slope conductance increased with time of exposure. In all neurones superfused with eserine for more than 60 min, burst discharges were observed. Burst discharges were blocked by atropine and Ni2+, but not by pirenzepine. 7. In cells superfused with eserine for more than 1 h, tetanic stimulation failed to elicit a slow EPSP or EPSC. Currents induced by focal acetylcholine (ACh) application were first enhanced by eserine, but blocked after exposure to eserine for more than 1 h. Blockade of ACh-induced currents was also observed after bath application of carbachol (CCh) in a concentration (0.2 microM) in which it did not induce an inward current at -60 mV holding potential. Further, the slow EPSP faded when elicited by repeated tetanic stimulation. 8. While the observed effects of eserine on hippocampal neurones can be explained by eserine's well-known ability to block acetylcholinesterase activity, our data indicate that the effects of eserine involve more than one muscarinic receptor site, i.e. desensitizing and non-desensitizing postsynaptic receptor sites.