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Muscarinic M₂ and M₁ Receptors Reduce GABA Release by Ca²⁺ Channel Modulation Through Activation of PI₃K/Ca²⁺-Independent and PLC/Ca²⁺-Dependent PKC

¹Laboratory of Synaptic and Cell Physiology, School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson Texas; and ²Department of Psychology, University of Texas at Arlington, Arlington, Texas

Submitted 17 January 2007; accepted in final form 15 June 2007

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 µM) or oxotremorine (10 µM) decreased the amplitude of electrically evoked 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 Ca²⁺ channel blockers -conotoxin GVIA (1 µM) or -AgaTx TK (200 nM) greatly blocked the muscarinic effect, suggesting that Ca²⁺-channels were target of the muscarinic modulation. The presence of the muscarinic M₂ receptor (M₂R) antagonists methoctramine (5 µM) or AF-DX 116 (1 µM) blocked most of the muscarinic evoked inhibitory postsynaptic current (eIPSC) reduction, indicating that M₂Rs were responsible for the effect, whereas the remaining component of the depression displayed M₁R-like sensitivity. Tissue preincubation with the specific blockers of phosphatidyl-inositol-3-kinase (PI₃K) wortmannin (200 nM), LY294002 (1 µM), or with the Ca²⁺-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 [GenBank] (10 µM). We conclude that acetylcholine release enhances the excitability of the auditory cortex by decreasing the release of GABA by inhibiting axonal V-dependent Ca²⁺ channels, mostly through activation of presynaptic M₂Rs/PI₃K/Ca²⁺-independent PKC pathway and—to a smaller extent—by the activation of M₁/PLC/Ca²⁺-dependent PKC.