title: Muscarinic M1 receptors modulate endotoxemia-induced loss of synaptic plasticity.
abstract: Septic encephalopathy is associated with rapid deterioration of cortical functions. Using magnetic resonance imaging (MRI) we detected functional abnormalities in the hippocampal formation of patients with septic delirium. Hippocampal dysfunction was further investigated in an animal model for sepsis using lipopolysaccharide (LPS) injections to induce endotoxemia in rats, followed by electrophysiological recordings in brain slices. Endotoxemia induced a deficit in long term potentiation which was completely reversed by apamin, a blocker of small conductance calcium-activated potassium (SK) channels, and partly restored by treatment with physostigmine (eserine), an acetylcholinesterase inhibitor, or TBPB, a selective M1 muscarinic acetylcholine receptor agonist. These results suggest a novel role for SK channels in the etiology of endotoxemia and explain why boosting cholinergic function restores deficits in synaptic plasticity. Drugs which enhance cholinergic or M1 activity in the brain may prove beneficial in treatment of septic delirium in the intensive care unit.
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. aleksandar.zivkovic@med.uni-heidelberg.de.
authors.forename: Aleksandar R
authors.initials: AR
authors.lastname: Zivkovic
authors.affiliation: Department of Radiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Sedlaczek
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: von Haken
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Brenner
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Weigand
authors.affiliation: Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
authors.forename: Hilmar
authors.initials: H
authors.lastname: Bading
authors.affiliation: Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany. bengtson@nbio.uniheidelberg.de.
authors.forename: C Peter
authors.initials: CP
authors.lastname: Bengtson
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hofer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D019540:Area Under Curve; D001703:Biophysics; D018678:Cholinergic Agents / Q000494:pharmacology; D038524:Diffusion Magnetic Resonance Imaging; D004195:Disease Models, Animal; D004558:Electric Stimulation; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D018805:Sepsis / Q000139:chemically induced / Q000473:pathology
chemical_list: D018678:Cholinergic Agents; D008070:Lipopolysaccharides; D043643:Receptor, Muscarinic M1; D001030:Apamin