IONIC MECHANISM OF THE SLOW AFTERDEPOLARIZATION INDUCED BY MUSCARINICRECEPTOR ACTIVATION IN RAT PREFRONTAL CORTEX

The mammalian prefrontal cortex receives a dense cholinergic innervati on from subcortical regions. We previously have shown that cholinergic stimulation of layer V pyramidal neurons of the rat prefrontal cortex results in a depolarizaton and the appearance of a slow afterdepolari zation (sADP). In the current report we examine the mechanism underlyi ng the sADP with the use of sharp microelectrode and whole cell record ing techniques in in vitro brain slices. The ability of acetylcholine (ACh) and carbachol to induce the appearance of an sADP in pyramidal c ells of layer V of prefrontal cortex is antagonized in a surmountable manner by atropine and is mimicked by application of muscarine or oxot remorine. These results indicate that ACh acts on muscarinic receptors to induce the sADP. In many cell types afterpotentials are triggered by calcium influx into the cell. Therefore we examined the possibility that calcium influx might be the trigger for the generation of the sA DP. Consistent with this possibility, buffering intracellular calcium reduced or abolished the sADP but had little effect on the direct musc arinic receptor-induced depolarization also seen in these cells. These results, coupled to the previous observation that calcium channel blo ckers inhibit the sADP, indicated that the sADP results from a rise in intracellular calcium secondary to calcium influx into the cell. The ionic basis for the current underlying the sADP (I-sADP) was examined with the use of ion substitution experiments. The amplitude of I-sADP was found to be reduced in a graded fashion by replacement of extracel lular sodium with N-methyl-D-glucamine (NMDG). In contrast no clear ev idence for the involvement of potassium or chloride channels in the: g eneration of the sADP or I-sADP could be found. This result indicated that I-sADP is carried by sodium iona flowing into the cell. However, the dependence of I-sADP on extracellular sodium was less pronounced t han expected for a pure sodium current. We interpret these results to indicate that the sADP is most likely mediated by nonselective cation channels. Examination of the current underlying the sADP at different voltages indicated that this current was also voltage dependent, turni ng off with hyperpolarization. We conclude that the sADP elicited by m uscarinic receptor activation in rat cortex is mediated predominantly by a calcium- and voltage-sensitive nonselective cation current. This current could represent an important mechanism through which ACh can r egulate neuronal excitability in prefrontal cortex.