Muscarinic facilitation of the occurrence of depolarization-induced suppression of inhibition in rat hippocampus.

Depolarization-induced suppression of inhibition is a transient decrease in GABAergic input to a hippocampal pyramidal cell following a brief depolarization of that cell. When recorded under whole-cell voltage clamp, monosynaptic, bicuculline-sensitive, GABA(A)-mediated currents are suppressed for a period lasting up to 1 min in response to a retrograde signal released by the pyramidal cell. The depolarization-induced suppression of inhibition process affects spontaneous, action-potential-dependent inhibitory postsynaptic currents, but suppression of these currents is seldom observed in the absence of carbachol, a cholinergic agonist. Because of the central roles played by cholinergic and GABAergic transmission in the regulation of hippocampal rhythmic activity, it will be important to understand the mechanism by which carbachol facilitates the appearance of depolarization-induced suppression of inhibition. As preliminary steps in the investigation of cholinergic actions on depolarization-induced suppression of inhibition, it is necessary to determine which cholinergic receptors are involved and the degree to which activation of these receptors is required for depolarization-induced suppression of inhibition. Nicotine did not mimic the effects of carbachol, and mecamylamine, a nicotinic receptor antagonist, did not block them. In contrast, the actions of carbachol were abolished by atropine and other muscarinic receptor antagonists. The actions of antagonists with relative selectivities for various subtypes of muscarinic receptors [4-diphenylacetoxy-N-methylpiperidine methiodide, pirenzepine, 11-([2-1-piperidinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzod iaz epine-6-one] suggested that cholinergic facilitation of the occurrence of depolarization-induced suppression of inhibition is likely to be mediated through muscarinic receptors of the M1 or M3 rather than M2 subtype. Despite its potent facilitation of the occurrence of depolarization-induced suppression of inhibition, muscarinic stimulation was not required for expression of depolarization-induced suppression of inhibition. Occasionally, depolarization-induced suppression of inhibition of spontaneous inhibitory postsynaptic currents occurred in the absence of carbachol and could not be blocked by atropine, and hence was not likely to be mediated by endogenous acetylcholine. Also, depolarization-induced suppression of inhibition of monosynaptically evoked inhibitory postsynaptic currents occurred without carbachol perfusion, and this was also insensitive to atropine. Therefore, the mechanism of depolarization-induced suppression of inhibition is not dependent on muscarinic receptor activation. Nevertheless, in vivo, septal cholinergic input to the hippocampus may provide the necessary activation of interneurons to allow depolarization-induced suppression of inhibition to occur.