M1 muscarinic receptor modulation of Kir2 channels enhances temporal summation of excitatory synaptic potentials in prefrontal cortex pyramidal neurons.
The cholinergic innervation of the prefrontal cortex (PFC) plays a pivotal role in regulating executive functions. Muscarinic receptors activated by acetylcholine depolarize pyramidal neurons in the rodent PFC homologue, but the mechanisms mediating this modulation are controversial. To address this question, we studied the responses of layer V rat pre- and infralimbic cortex pyramidal neurons to muscarinic receptor stimulation. Consistent with previous findings, M(1) receptor stimulation produced a strong depolarization, leading to tonic firing. Voltage-clamp analysis revealed that M(1) activation reduced constitutively active inwardly rectifying (Kir2) K(+) channel currents. Blocking protein kinase C activation or depleting intracellular Ca(2+) stores did not affect the modulation. However, reversal of the modulation was prevented by the phosphoinositide kinase inhibitor, wortmanin, suggesting the modulation was mediated by depletions of membrane phosphatidylinositol-4,5-bisphosphate (PIP(2)). Reduction of Kir2 channel currents by M(1) receptor stimulation significantly increased the temporal summation of excitatory synaptic potentials (EPSPs) evoked by repetitive stimulation of layer I. This action was complimented by M(2/4) receptor mediated presynaptic inhibition of the same terminals. As a consequence of this dual modulation, the responses to a single, isolated afferent volley was reduced, but the response to a high-frequency afferent burst was potentiated.
Carr
David B
DB
Dept. of Neuroscience, Medical University of South Carolina, Charleston, USA.
Surmeier
D James
DJ
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D053119:Benzophenanthridines / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D018679:Cholinergic Agonists / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation; D004791:Enzyme Inhibitors; D004963:Estrenes / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010890:Pirenzepine / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology*; D011189:Potassium Chloride / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000502:physiology*
D000470:Alkaloids; D053119:Benzophenanthridines; D018679:Cholinergic Agonists; D004791:Enzyme Inhibitors; D004963:Estrenes; C489461:Kir2.1 channel; D018727:Muscarinic Antagonists; D024661:Potassium Channels, Inwardly Rectifying; D011760:Pyrrolidinones; D043643:Receptor, Muscarinic M1; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D010890:Pirenzepine; D011189:Potassium Chloride; D002217:Carbachol; C016299:chelerythrine