title: Butyrylcholinesterase and the control of synaptic responses in acetylcholinesterase knockout mice.
abstract: At the neuromuscular junction (NMJ) acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) can hydrolyze acetylcholine (ACh). Released ACh quanta are known to diffuse rapidly across the narrow synaptic cleft and pairs of ACh molecules cooperate to open endplate channels. During their diffusion through the cleft, or after being released from muscle nicotinic ACh receptors (nAChRs), most ACh molecules are hydrolyzed by AChE highly concentrated at the NMJ. Advances in mouse genomics offered new approaches to assess the role of specific cholinesterases involved in synaptic transmission. AChE knockout mice (AChE-KO) provide a valuable tool for examining the complete abolition of AChE activity and the role of BChE. AChE-KO mice live to adulthood, and exhibit an increased sensitivity to BChE inhibitors, suggesting that BChE activity facilitated their survival and compensated for AChE function. Our results show that BChE is present at the endplate region of wild-type and AChE-KO mature muscles. The decay time constant of focally recorded miniature endplate currents was 1.04 +/- 0.06 ms in wild-type junctions and 5.4 ms +/- 0.3 ms in AChE-KO junctions, and remained unaffected by BChE-specific inhibitors, indicating that BChE is not limiting ACh duration on endplate nAChRs. Inhibition of BChE decreased evoked quantal ACh release in AChE-KO NMJs. This reduction in ACh release can explain the greatest sensitivity of AChE-KO mice to BChE inhibitors. BChE is known to be localized in perisynaptic Schwann cells, and our results strongly suggest that BChE's role at the NMJ is to protect nerve terminals from an excess of ACh.
authors.affiliation: CNRS, Institut de Neurobiologie Alfred Fessard, FRC2118, Laboratoire de Neurobiologie Cellulaire et Moléculaire, UPR 9040, 1, avenue de la Terrasse, Gif sur Yvette, F-91198, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Girard
authors.forename: Véronique
authors.initials: V
authors.lastname: Bernard
authors.forename: Jasmina
authors.initials: J
authors.lastname: Minic
authors.forename: Arnaud
authors.initials: A
authors.lastname: Chatonnet
authors.forename: Eric
authors.initials: E
authors.lastname: Krejci
authors.forename: Jordi
authors.initials: J
authors.lastname: Molgó
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002093:Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004594:Electrophysiology; D005260:Female; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009045:Motor Endplate / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D009469:Neuromuscular Junction / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013770:Tetraisopropylpyrophosphamide / Q000494:pharmacology; D013997:Time Factors
chemical_list: D002800:Cholinesterase Inhibitors; D002093:Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide; D013770:Tetraisopropylpyrophosphamide; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase