title: Muscarinic acetylcholine receptor-mediated effects in slices from human epileptogenic cortex.
abstract: Acetylcholine has been implicated in higher cortical functions such as learning, memory and cognition, yet the cellular effects of muscarinic acetylcholine receptor (mAChR) activation are poorly understood in the human cortex. Here we investigated the effect of the mAChR agonist carbachol (CCh) and various mAChR antagonists in human cortical slices (from tissue removed during neurosurgical treatment of epilepsy) by intracellular and extracellular recordings. CCh increased neuronal firing, which was antagonised by atropine (non-selective mAChR antagonist) and pirenzepine (M(1)/M(4) mAChRs antagonist) when applied before or after CCh application. AF-DX 116 (M(2)/M(4) mAChRs antagonist) had no effect on CCh-induced increase of firing. CCh also reduced evoked excitatory postsynaptic potentials (EPSP), and the CCh-induced depression of EPSP was fully reversed by atropine. Pirenzepine reversed the depression of CCh on EPSP, but failed to prevent the depression when applied before CCh. AF-DX 116 prevented the CCh-induced depression of evoked EPSP when applied before CCh. CCh also depressed GABAergic transmission and this effect was antagonised by AF-DX 116. Xanomeline (M(1)/M(4) mAChR agonist) increased neuronal firing and decreased EPSP, but had no effect on GABAergic transmission. Reduction (with linopirdine) and enhancement (with retigabine) of the M-current (mediated by K(V)7 channels), increased and decreased neuronal firing, respectively, but had marginal effects on the evoked EPSP. Our results indicate that three pharmacologically distinct mAChRs modulate neuronal firing, glutamatergic and GABAergic transmissions in the human epileptogenic neocortex. The data are discussed towards possible implications of altered mAChR signalling in hyperexcitability and cognitive functions in the human neocortex.
authors.affiliation: Charité Universitätsmedizin Berlin, Centre for Anatomy, Institute for Cell Biology and Neurobiology, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Gigout
authors.forename: S
authors.initials: S
authors.lastname: Wierschke
authors.forename: T-N
authors.initials: TN
authors.lastname: Lehmann
authors.forename: P
authors.initials: P
authors.lastname: Horn
authors.forename: C
authors.initials: C
authors.lastname: Dehnicke
authors.forename: R A
authors.initials: RA
authors.lastname: Deisz
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000328:Adult; D001703:Biophysics; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004338:Drug Combinations; D004558:Electric Stimulation; D004827:Epilepsy / Q000473:pathology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: D018679:Cholinergic Agonists; D004338:Drug Combinations; D018727:Muscarinic Antagonists; D011725:Pyridines; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; D010890:Pirenzepine; D002217:Carbachol; C075257:xanomeline; C048593:otenzepad