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Vol. 293, Issue 3, 896-902, June 2000

Postnatal Developmental Delay and Supersensitivity to Organophosphate in Gene-Targeted Mice Lacking Acetylcholinesterase1

Weihua Xie , Judith A. Stribley , Arnaud Chatonnet, Phillip J. Wilder, Angie Rizzino , Rodney D. McComb, Palmer Taylor, Steven H. Hinrichs and Oksana Lockridge

Eppley Institute (W.X., J.A.S., P.J.W., A.R., S.H.H., O.L.), Department of Biochemistry and Molecular Biology (W.X., A.R., O.L.), and Department of Pathology and Microbiology (J.A.S., A.R., R.D.M., S.H.H.), University of Nebraska Medical Center, Omaha, Nebraska; Departement de Physiologie Animale, Institut National de la Recherche Agronomique, Montpellier, France (A.C.); and Department of Pharmacology, University of California at San Diego, La Jolla, California (P.T.)

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.

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.

0022-3565/00/2933-0896$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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