MUSCARINIC DEPRESSION OF SYNAPTIC TRANSMISSION AT THE HIPPOCAMPAL MOSSY FIBER SYNAPSE

1. The action of muscarine was studied in the CA3 region of the rat hippocampal slice with single-electrode voltage-clamp techniques. 2. Bath application of 1 or 10 μM muscarine produced an increase in the input resistance of these cells and reduced the slow afterhyperpolarization (sAHP) response. Changes in input resistance were more pronounced around the resting potential of the cell (-50 to -60 mV), but in many cells an effect was also seen at -80 mV. These effects were absent when cesium chloride-containing microelectrodes were used. 3. At 1 μM, muscarine had little effect on synaptic transmission, causing a 0 ± 7% (mean ± SE, n = 19) change in excitatory postsynaptic potential (EPSP) and decreasing the excitatory postsynaptic current (EPSC) by 11 ± 6% (n = 14); neither change was statistically significant. 4. In contrast, 10 μM muscarine produced a reliable depression of both the EPSP and EPSC. This effect was independent of the electrolyte used: with KCl the EPSP was depressed 23 ± 4% (n = 5) and the EPSC 35 ± 5% (n = 4); for CsCl the EPSP was depressed 23 ± 10% (n = 7) and the EPSC 34 ± 5% (n = 7). 5. Muscarine did not alter the reversal potential of the synaptic current but merely produced a decrease in slope conductance (37 ± 5%, n = 6). 6. Muscarine did not significantly alter the shape of the EPSC waveform. This was assessed by comparing the 10-90% rise time and the half decay time of the current before and after muscarine. 7. A nine-compartment model of a CA3 pyramidal cell was studied. We found that postsynaptic alterations in membrane resistivity have comparatively little effect on EPSP amplitude. 8. The hypothesis that muscarinic agonists depress synaptic transmission by acting postsynaptically has been tested under conditions of voltage clamp. Our data argue against the possibility that muscarine decreases the EPSP through changes in postsynaptic membrane resistivity or by altering the reversal potential of the synaptic current. The possibility that muscarine can modulate the sensitivity of glutamate receptors or alter spine morphology cannot be ruled out, but a presynaptic site of action for muscarine appears the most likely explanation for our results.