Reduced Acetylcholine Receptor Density, Morphological Remodeling, and Butyrylcholinesterase Activity Can Sustain Muscle Function in Acetylcholinesterase Knockout Mice

Abstract

Nerve-evoked contractions were studied in vitro in phrenic nerve-hemidiaphragm preparations from strain 129X1 acetyloholinesterase knockout (AChE-/-) 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 diaphragms of AChE-/- mice by single supramaximal stimuli had larger amplitudes and slower rise and decay times than did those in wild-type animals. In AChE-/- preparations, repetitive stimulation at frequencies of 20 and 50 Hz and at 200 and 400 Hz produced decremental muscle tensions; however, stimulation at 70 and 100 Hz resulted in little or no loss of tension during trains. Muscles from AChE+/+ mice maintained tension at all frequencies examined but exhibited tetanic fade after exposure to the selective AChE inhibitor 1,5-bis(4-allyldim- ethyl-ammoniumphenyl)pentane-3-one (BW 284C51). The ability of diaphragm muscles from AChE-/- mice to maintain tension at 70 and 100 Hz suggests a partial compensation for impairment of acetylcholine (ACh) hydrolysis. Three mechanisms-including a reliance on BChE activity for termination of ACh action, downregulation of nicotinic acetylcholine receptors (nAChRs), and morphological remodeling of the endplate region-were identified. Studies of neuromuscular transmission in this model system provide an excellent opportunity to evaluate the role of AChE without complications arising from use of inhibitors.

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Document Details

Document Type
Technical Report
Publication Date
Sep 01, 2004
Accession Number
ADA442463

Entities

People

  • Ellen G. Duysen
  • George Oyler
  • Heather A. Manley
  • Michael Adler
  • Oksana Lockridge
  • Robert E. Sheridan
  • Robert K. Kan
  • Sharad S. Deshpande
  • Tracey A. Hamilton

Organizations

  • United States Army Medical Research Institute of Chemical Defense

Tags

Communities of Interest

  • Biomedical

DTIC Thesaurus Topics

  • Acetylcholinesterases
  • Animals
  • Biomedical Research
  • Cells
  • Confocal Microscopy
  • Data Analysis
  • Electron Microscopy
  • Enzymes
  • Microscopy
  • Muscle Fibers
  • Nerve Agents
  • Peripheral Nervous System
  • Phrenic Nerves
  • Rodents
  • Skeletal Muscle
  • Smooth Muscle
  • Synapses

Fields of Study

  • Biology

Readers

  • Cardiovascular Physiology
  • Molecular and Cellular Biology
  • Neurotoxicology