SUSTAIN MUSCLE FUNCTION IN ACETYLCHOLINESTERASE KNOCKOUT MICE

ABSTRACT: Nerve-evoked contractions were studied in vitro in phrenicnerve-hemidiaphragm preparations from strain 129X1 acetylcholinesteraseknockout (AChE-1-) mice and their wild-type littermates (AChE+/+). The AChE--mice fail to express AChE but have normal levels of butyrylcholinesterase(BChE) and can survive into adulthood. Twitch tensions elicited in diaphragmsof AChE-'- mice by single supramaximal stimuli had larger amplitudes andslower rise and decay times than did those in wild-type animals. In AChE-1-preparations, repetitive stimulation at frequencies of 20 and 50 Hz and at 200and 400 Hz produced decremental muscle tensions; however, stimulation at 70and 100 Hz resulted in little or no loss of tension during trains. Muscles fromAChE+'1 mice maintained tension at all frequencies examined but exhibitedtetanic fade after exposure to the selective AChE inhibitor 1,5-bis(4-allyldim-ethyl-ammoniumphenyl)pentane-3-one (BW 284C51). The ability of diaphragmmuscles from AChE-- mice to maintain tension at 70 and 100 Hz suggests apartial compensation for impairment of acetylcholine (ACh) hydrolysis. Threemechanisms-including a reliance on BChE activity for termination of AChaction, downregulation of nicotinic acetylcholine receptors (nAChRs), and mor-phological remodeling of the endplate region-were identified. Studies of neu-romuscular transmission in this model system provide an excellent opportunityto evaluate the role of AChE without complications arising from use of inhibitors.Muscle Nerve 30: 317-327, 2004