Updated 5 January 2009

General Information

Transgene: A targeting vector was designed to replace exons 2-5 of the endogenous gene with a neomycin resistance gene. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells (line 3D6) were injected into C57BL/6 blastocysts. The resulting chimeric males were bred to 129S6/SvEvTac females.

Mutation: Targeted mutation 1

Breeding: Heterozygous pups were bred to 129S6/SvEvTac for more than 10 generations before arrival at The Jackson Laboratory.

TJL mating system: heterozygote x +/+ sibling (female x male). Homozygous mice do not reproduce. A high fat diet is necessary for gestation of homozygous pups from Het x wt matings.

Mouse strain: 129-Ache^tm1Loc/J

Phenotype

Neuropathological Analysis:

Deletion of four exons of the AChE gene reduced AChE activity by half in het-mutant mice and totally eliminated AChE activity in null animals.

Normal neuromuscular junction of 12-day-old null animals.

Respiratory motor-neurons are protected from the tonic activity induced by cholinergic agonists.

Homozygous mice have drastic reduction of the M1, M2, and M4 muscarinic acetylcholine receptors in the cortex and hippocampus with decreased cell surface localization and increased intracellular localization of these receptors.

Homozygous mice have defective formation of the inner retina associated with apoptotic photoreceptor degeneration with age.

Behavioral Phenotype:

Homozygous mice have 25% fetal mortality. Those born have retarded growth, fine motor tremors, unusual posture and gait, no righting reflex, malformed pinna, and sealed eyelids. These mice die emaciated and dehydrated by 3 weeks of age (day 21).

Homozygous mice are hypersensitive to organophosphates and bambuterol. Symptoms of organophosphate poisoning include pulsating paws, body tremor, abnormal gait, pinpoint pupils, muscle weakness, and early death following seizure. When restrained, a white mucus forms on the eyes and seizures may occur.

Mice also have several developmental delays, low body mass, decreased pain response, sexual dysfunction, an inability to chew solid food, and a lack of aggression.

Null mice develop fine motor tremor at day 3 or 4 leading to gait abnormalities and erratic motion (continuous circling).

Heterozygous mice are viable and fertile with normal maturation and development. They exhibit intermediate sensitivity to organophosphates and are unaffected by bambuterol.

Availability

Contact: The Jackson Lab, cryopreserved, stock #005987.

References

Primary:

Xie W, Wilder PJ, Stribley J, Chatonnet A, Rizzino A, Taylor P, Hinrichs SH, Lockridge O. Knockout of one acetylcholinesterase allele in the mouse. Chem Biol Interact. 1999 May 14;119-120():289-99. Abstract

Associated:

Bytyqi AH, Lockridge O, Duysen E, Wang Y, Wolfrum U, Layer PG. Impaired formation of the inner retina in an AChE knockout mouse results in degeneration of all photoreceptors. Eur J Neurosci. 2004 Dec;20(11):2953-62. Abstract

Chatonnet F, Boudinot E, Chatonnet A, Taysse L, Daulon S, Champagnat J, Foutz AS. Respiratory survival mechanisms in acetylcholinesterase knockout mouse. Eur J Neurosci. 2003 Sep;18(6):1419-27. Abstract

Cousin X, Strahle U, Chatonnet A. Are there non-catalytic functions of acetylcholinesterases? Lessons from mutant animal models. Bioessays. 2005 Feb;27(2):189-200. Abstract

Duysen EG, Li B, Xie W, Schopfer LM, Anderson RS, Broomfield CA, Lockridge O. Evidence for nonacetylcholinesterase targets of organophosphorus nerve agent: supersensitivity of acetylcholinesterase knockout mouse to VX lethality. J Pharmacol Exp Ther. 2001 Nov;299(2):528-35. Abstract

Duysen EG, Stribley JA, Fry DL, Hinrichs SH, Lockridge O. Rescue of the acetylcholinesterase knockout mouse by feeding a liquid diet; phenotype of the adult acetylcholinesterase deficient mouse. Brain Res Dev Brain Res. 2002 Jul 30;137(1):43-54. Abstract

Li B, Duysen EG, Volpicelli-Daley LA, Levey AI, Lockridge O. Regulation of muscarinic acetylcholine receptor function in acetylcholinesterase knockout mice. Pharmacol Biochem Behav. 2003 Mar;74(4):977-86. Abstract

Li B, Stribley JA, Ticu A, Xie W, Schopfer LM, Hammond P, Brimijoin S, Hinrichs SH, Lockridge O. Abundant tissue butyrylcholinesterase and its possible function in the acetylcholinesterase knockout mouse. J Neurochem. 2000 Sep;75(3):1320-31. Abstract

Volpicelli-Daley LA, Hrabovska A, Duysen EG, Ferguson SM, Blakely RD, Lockridge O, Levey AI. Altered striatal function and muscarinic cholinergic receptors in acetylcholinesterase knockout mice. Mol Pharmacol. 2003 Dec;64(6):1309-16. Abstract