title: An acetylcholinesterase inhibitor, eserine, induces long-term depression at CA3-CA1 synapses in the hippocampus of adult rats.
abstract: Studies in humans and rodents support a role for muscarinic ACh receptor (mAChR) and nicotinic AChR in learning and memory, and both regulate hippocampal synaptic plasticity using complex and often times opposing mechanisms. Acetylcholinesterase (AChE) inhibitors are commonly prescribed to enhance cholinergic signaling in Alzheimer's disease in hopes of rescuing cognitive function, caused, in part, by degeneration of cholinergic innervation to the hippocampus and cortex. Unfortunately, therapeutic efficacy is moderate and inconsistent, perhaps due to unanticipated mechanisms. M1 mAChRs bidirectionally control synaptic strength at CA3-CA1 synapses; weak pharmacological activation using carbachol (CCh) facilitates potentiation, whereas strong agonism induces muscarinic long-term depression (mLTD) via an ERK-dependent mechanism. Here, we tested the prediction that accumulation of extracellular ACh via inhibition of AChE is sufficient to induce LTD at CA3-CA1 synapses in hippocampal slices from adult rats. Although AChE inhibition with eserine induces LTD, it unexpectedly does not share properties with mLTD induced by CCh, as reported previously. Eserine-LTD was prevented by the M3 mAChR-preferring antagonist 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), and pharmacological inhibition of MEK was completely ineffective. Additionally, pharmacological inhibition of p38 MAPK prevents mLTD but has no effect on eserine-LTD. Finally, long-term expression of eserine-LTD is partially dependent on a decrease in presynaptic release probability, likely caused by tonic activation of mAChRs by the sustained increase in extracellular ACh. Thus these findings extend current literature by showing that pharmacological AChE inhibition causes a prolonged decrease in presynaptic glutamate release at CA3-CA1 synapses, in addition to inducing a likely postsynaptic form of LTD.
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama; Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Robert Alan
authors.initials: RA
authors.lastname: Mans
authors.affiliation: Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Warmus
authors.affiliation: Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Smith
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama; Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama; and mcmahon@uab.edu.
authors.forename: Lori L
authors.initials: LL
authors.lastname: McMahon
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000502:physiology; D056654:CA3 Region, Hippocampal / Q000187:drug effects* / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D046509:Tissue Culture Techniques; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D018727:Muscarinic Antagonists; D010880:Piperidines; D043587:Receptor, Muscarinic M3; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D010830:Physostigmine; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D000109:Acetylcholine
keywords: Alzheimer's disease; acetylcholinesterase inhibitor; hippocampus; long-term depression; muscarinic AChR