Postnatal Developmental Delay and Supersensitivity to Organophosphate in Gene-Targeted Mice Lacking Acetylcholinesterase1
- Weihua Xie1,2,
- Judith A. Stribley1,3,
- Arnaud Chatonnet4,
- Phillip J. Wilder1,
- Angie Rizzino1,2,3,
- Rodney D. McComb3,
- Palmer Taylor5,
- Steven H. Hinrichs1,3 and
- Oksana Lockridge1,2
- 1Eppley Institute (W.X., J.A.S., P.J.W., A.R., S.H.H., O.L.),2Department of Biochemistry and Molecular Biology (W.X., A.R., O.L.), and 3Department of Pathology and Microbiology (J.A.S., A.R., R.D.M., S.H.H.), University of Nebraska Medical Center, Omaha, Nebraska;4Departement de Physiologie Animale, Institut National de la Recherche Agronomique, Montpellier, France (A.C.); and 5Department of Pharmacology, University of California at San Diego, La Jolla, California (P.T.)
Abstract
Acetylcholinesterase (AChE; EC 3.1.1.7) is the primary terminator of nerve impulse transmission at cholinergic synapses and is believed to play an important role in neural development. Targeted deletion of four exons of the ACHE gene reduced AChE activity by half in heterozygous mutant mice and totally eliminated AChE activity in nullizygous animals. Butyrylcholinesterase (EC 3.1.1.8) activity was normal in AChE −/− mice. Although nullizygous mice were born alive and lived up to 21 days, physical development was delayed. The neuromuscular junction of 12-day-old nullizygous animals appeared normal in structure. Nullizygous mice were highly sensitive to the toxic effects of the organophosphate diisopropylfluorophosphate and to the butyrylcholinesterase-specific inhibitor bambuterol. These findings indicate that butyrylcholinesterase and possibly other enzymes are capable of compensating for some functions of AChE and that the inhibition of targets other than AChE by organophosphorus agents results in death.
Footnotes
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Send reprint requests to: Dr. Oksana Lockridge, University of Nebraska Medical Center, Eppley Institute, 986805 Nebraska Medical Center, Omaha, NE 68198-6805. E-mail:olockrid{at}unmc.edu
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↵1 This work was supported by U.S. Army Medical Research and Materiel Command DAMD 17-94-J-4005 and DAMD 17-97-1-7349 (to O.L.), Association Francaise Contre les Myopathies (MNM1997) (A.C.), Nebraska State Research Initiative (S.H.H., A.R.), University of Nebraska Medical Center Seed Grant 98-005 (O.L.), and U.S. Public Health Service Grants GM18360 (P.T.) and R01-DA011707 (O.L.). Core facilities of the University of Nebraska Medical Center Cancer Center used in this work were supported in part by a Center Grant from the National Cancer Institute (Laboratory Cancer Research Center Support Grant CA36727). The opinions or assertions contained herein belong to the authors and should not be construed as the official views of the U.S. Army or the Department of Defense.
- Abbreviations:
- AChE
- acetylcholinesterase enzyme
- ACHE
- acetylcholinesterase gene
- BChE
- butyrylcholinesterase enzyme
- DFP
- diisopropylfluorophosphate
- iso-OMPA
- tetraisopropylpyrophosphoramide
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- Received November 29, 1999.
- Accepted January 28, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
