title: Chronic acetylcholinesterase overexpression induces multilevelled aberrations in mouse neuromuscular physiology.
abstract: Chronic overexpression of the acetylcholine-hydrolysing enzyme acetylcholinesterase (AChE) is a notable consequence of exposure to anticholinesterase drugs or poisons. However, the physiological consequences for the resultant neuromuscular disfunction have not yet been carefully analysed. Here we report detailed dissection of the different components of neuromuscular function in transgenic mice previously shown to display motor fatigue and altered muscle morphology as a consequence of neuronal overexpression of AChE-S, the synaptic AChE variant. Transgenic diaphragm muscle presented exaggerated fatigue as a combined consequence of neurotransmission fading and muscle mechanical malfunctioning. In a tetanic stimulation protocol, transgenic muscles rapidly fatigued to a larger extent than wild-type muscles, when stimulated either directly or via the phrenic nerve. AChE overexpression involved moderate but significant aberrations of synaptic transmission with higher quantal content (measured at 0.2 mM Ca(2+), 2.3 mM Mg(2+)). Furthermore, treatment with the anti-cholinesterase physostigmine revealed a higher amplitude and half-decay time of the transgenic quantal postsynaptic response. Our observations imply that elevated levels of neuronal AChE-S are expected to cause muscle exhaustion due to a combination of modest, multilevelled aberrations in synaptic transmission, muscle function and morphology.
authors.affiliation: Department of Neurobiology, Institute of Life Sciences, Hebrew University of Jerusalem, Israel 91904.
authors.forename: Noa
authors.initials: N
authors.lastname: Farchi
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
authors.forename: Binyamin
authors.initials: B
authors.lastname: Hochner
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D003964:Diaphragm / Q000503:physiopathology; D004558:Electric Stimulation; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D018763:Muscle Fatigue; D009469:Neuromuscular Junction / Q000503:physiopathology*; D010641:Phenotype; D010791:Phrenic Nerve / Q000503:physiopathology; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission; D013997:Time Factors
chemical_list: D000110:Acetylcholinesterase