Two distinct and activity-dependent mechanisms contribute to autoreceptor-mediated inhibition of GABAergic afferents to hilar mossy cells

We report that bath application of 3 mu m carbachol (CCh), a muscarinic acetylcholine receptor agonist, reduces evoked IPSC amplitude recorded from hilar mossy cells in the rat dentate gyrus through a presynaptic mechanism. While CCh has been shown to inhibit evoked IPSCs in other systems, this effect is intriguing in that it does not require inhibitory action of either presynaptic muscarinic receptors or presynaptic cannabinoid receptors. Previous work from our lab has shown that identical application of CCh produces an action potential-dependent increase in ambient GABA in this system; however, inhibition of evoked IPSCs produced by both 3 and 10 mu m CCh is insensitive to the GABA(B) antagonist CGP52432. Therefore we hypothesized that CCh-mediated inhibition of evoked IPSCs might be produced by activity-dependent increases in ambient GABA and subsequent activation of presynaptic GABA(A) receptors. Consistent with that hypothesis, we report that CCh-mediated inhibition of evoked IPSCs appears to be well correlated with CCh-mediated facilitation of spontaneous IPSCs and that CCh does not affect GABA(B)-mediated IPSCs recorded in the presence of the GABA(A) receptor antagonist picrotoxin. Intriguingly, however, we found that bath application of the GAT-1 transport blocker NO-711 (1 mu m) produces inhibition of evoked IPSCs that is reversed by CGP52432, and that lower doses of CCh produce inhibition with greater CGP52432 sensitivity. These observations, combined with subsequent work on multiple pulse depression, reveal that feedback inhibition of GABAergic afferents to hilar mossy cells is governed by a complex relationship between two distinct and activity-dependent mechanisms.