Protein kinase C mediates muscarinic block of intrinsic bursting in rat hippocampal neurons

1. Acetylcholine released from basal forebrain cholinergic fibres suppresses intrinsic bursting in cortical pyramidal cells through activation of muscarinic receptors. The signal transduction pathway mediating this action is not known. We used intracellular recordings from CA1 pyramidal cells in hippocampal slices to investigate the involvement of protein kinase C (PKC) in this cholinergic function. 2. Bath-applied carbachol (CCh; 5 mu M) consistently suppressed intrinsic bursting in an atropine-sensitive (1 mu M) manner. 3. Intrinsic bursting was suppressed by 4 beta-phorbol 12,13-dibutyrate (PDBu; 5-10 mu M), a potent PKC activator, but not by the inactive phorbol ester 4 alpha-phorbol 12,13-didecanoate (PDC; 50 mu M). Prior application of the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7; 10 mu M) extracellularly or intracellularly prevented the PDBu effect. 4. Pretreatment with H7, but not with the broad-spectrum kinase inhibitor N-(2-guanidino-ethyl)-5-isoquinoline-sulfonyl hydrochloride (HA1004; 10 mu M), prevented the CCh-induced suppression of bursting. 5. The active component of the spike after-depolarization (ADP) was reduced by CCh in an atropine-sensitive manner. This effect was mimicked by PDBu, but not by PDC. It was prevented by pretreatment with H7, but not with HA1004. 6. Blocking most K+ currents with Ca2+-free , TEA-containing saline induced large TTX-sensitive plateau potentials lasting > 150 ms, driven by a persistent Na+ current. These potentials were suppressed by PDBu, but not by PDC. Pretreatment with H7 prevented the PDBu-induced suppression of the plateau potentials. 7. We conclude that cholinergic suppression of intrinsic bursting in hippocampal CA1 pyramidal cells is mediated by muscarinic activation of PKC, which down-regulates the persistent Na+ current underlying slow depolarizing potentials in these neurons.