receptors reduce GABA release by Ca 2ϩ channel modulation through activation of PI 3 K/Ca 2ϩ -independent and PLC/Ca 2ϩ -dependent PKC. J Neurophysiol 98: [952][953][954][955][956][957][958][959][960][961][962][963][964][965] 2007. First We measured pharmacologically isolated GABAergic currents from layer II/III neurons of the rat auditory cortex using patch-clamp recording. Activation of muscarinic receptors by muscarine (1 M) or oxotremorine (10 M) decreased the amplitude of electrically

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... d inhibitory postsynaptic currents to about one third of their control value. Neither miniature nor exogenously evoked GABAergic currents were altered by the presence of muscarinic agonists, indicating that the effect was spike-dependent and not mediated postsynaptically. The presence of the N-or P/Q-type Ca 2ϩ channel blockers -conotoxin GVIA (1 M) or -AgaTx TK (200 nM) greatly blocked the muscarinic effect, suggesting that Ca 2ϩ -channels were target of the muscarinic modulation. The presence of the muscarinic M 2 receptor (M 2 R) antagonists methoctramine (5 M) or AF-DX 116 (1 M) blocked most of the muscarinic evoked inhibitory postsynaptic current (eIPSC) reduction, indicating that M 2 Rs were responsible for the effect, whereas the remaining component of the depression displayed M 1 R-like sensitivity. Tissue preincubation with the specific blockers of phosphatidyl-inositol-3-kinase (PI 3 K) wortmannin (200 nM), LY294002 (1 M), or with the Ca 2ϩ -dependent PKC inhibitor Gö 6976 (200 nM) greatly impaired the muscarinic decrease of the eIPSC amplitude, whereas the remaining component was sensitive to preincubation in the phospholipase C blocker U73122 (10 M). We conclude that acetylcholine release enhances the excitability of the auditory cortex by decreasing the release of GABA by inhibiting axonal V-dependent Ca 2ϩ channels, mostly through activation of presynaptic M 2 Rs/PI 3 K/Ca 2ϩ -independent PKC pathway and-to a smaller extent-by the activation of M 1 /PLC/ Ca 2ϩ -dependent PKC.